NM_003200.5(TCF3):c.1541C>T (p.Ser514Leu) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 11, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001357946.4

Allele description

NM_003200.5(TCF3):c.1541C>T (p.Ser514Leu)

Gene:

TCF3:transcription factor 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_003200.5(TCF3):c.1541C>T (p.Ser514Leu)

HGVS:

NC_000019.10:g.1615731G>A
NG_029953.2:g.41816C>T
NM_001136139.4:c.1541C>T
NM_001351778.2:c.1538C>T
NM_001351779.2:c.1541C>T
NM_003200.5:c.1541C>TMANE SELECT
NP_001129611.1:p.Ser514Leu
NP_001338707.1:p.Ser513Leu
NP_001338708.1:p.Ser514Leu
NP_003191.1:p.Ser514Leu
LRG_1325t1:c.1541C>T
LRG_1325t2:c.1541C>T
LRG_1325:g.41816C>T
LRG_1325p1:p.Ser514Leu
LRG_1325p2:p.Ser514Leu
NC_000019.9:g.1615730G>A
NM_003200.3:c.1541C>T

Protein change:

S513L

Links:

dbSNP: rs372168347

NCBI 1000 Genomes Browser:

rs372168347

Molecular consequence:

NM_001136139.4:c.1541C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351778.2:c.1538C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351779.2:c.1541C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003200.5:c.1541C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Homo sapiens interferon regulatory factor 1 isoform I4 (IRF1) mRNA, complete cds...
Homo sapiens interferon regulatory factor 1 isoform I4 (IRF1) mRNA, complete cds, alternatively spliced
gi|540849918|gb|KC209828.1|

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Homo sapiens interferon regulatory factor 1 isoform d78 (IRF1) mRNA, complete cd...
Homo sapiens interferon regulatory factor 1 isoform d78 (IRF1) mRNA, complete cds, alternatively spliced
gi|540849901|gb|KC209827.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001553559	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV002252848	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34618307, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001553559

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV002252848

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 11, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Primary antibody deficiencies in Turkey: molecular and clinical aspects.

Firtina S, Ng YY, Ng OH, Kiykim A, Ozek EY, Kara M, Aydiner E, Nepesov S, Camcioglu Y, Sayar EH, Gungoren EY, Reisli I, Torun SH, Haskologlu S, Cogurlu T, Kaya A, Cekic S, Baris S, Ozbek U, Ozen A, Sayitoglu M.

Immunol Res. 2022 Feb;70(1):44-55. doi: 10.1007/s12026-021-09242-z. Epub 2021 Oct 7. Erratum in: Immunol Res. 2022 Feb;70(1):134. doi: 10.1007/s12026-021-09248-7.

PubMed [citation]

PMID:: 34618307

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553559.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The TCF3 p.Ser514Leu variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs372168347) and in control databases in 1 of 31366 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017) and was observed in the following population: East Asian in 1 of 1560 chromosomes (freq: 0.000641), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ser514 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002252848.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 514 of the TCF3 protein (p.Ser514Leu). This variant is present in population databases (rs372168347, gnomAD 0.01%). This missense change has been observed in individual(s) with agammaglobulinemia (PMID: 34618307). This variant is also known as c.1388C>T. ClinVar contains an entry for this variant (Variation ID: 1050473). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TCF3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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