NM_000135.4(FANCA):c.4185dup (p.Ile1396fs) AND Fanconi anemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 6, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001349630.9

Allele description [Variation Report for NM_000135.4(FANCA):c.4185dup (p.Ile1396fs)]

NM_000135.4(FANCA):c.4185dup (p.Ile1396fs)

Genes:

FANCA:FA complementation group A [Gene - OMIM - HGNC]
ZNF276:zinc finger protein 276 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_000135.4(FANCA):c.4185dup (p.Ile1396fs)

HGVS:

NC_000016.10:g.89738957dup
NG_011706.1:g.82701dup
NM_000135.4:c.4185dupMANE SELECT
NM_001113525.2:c.*711dupMANE SELECT
NM_001286167.3:c.4189dup
NM_152287.4:c.*711dup
NP_000126.2:p.Ile1396Aspfs
NP_000126.2:p.Ile1396fs
NP_001273096.1:p.Asp1397fs
LRG_495t1:c.4185dup
LRG_495:g.82701dup
LRG_495p1:p.Ile1396Aspfs
NC_000016.9:g.89805364_89805365insC
NC_000016.9:g.89805365dup
NM_000135.2:c.4185dup
NM_000135.4:c.4185dupGMANE SELECT
NR_110122.2:n.2711dup
NR_110126.2:n.2594dup
NR_110128.2:n.2534dup
NR_110129.2:n.2628dup

Protein change:

D1397fs

Links:

dbSNP: rs2062046121

NCBI 1000 Genomes Browser:

rs2062046121

Molecular consequence:

NM_001113525.2:c.*711dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152287.4:c.*711dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000135.4:c.4185dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001286167.3:c.4189dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_110122.2:n.2711dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110126.2:n.2594dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110128.2:n.2534dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_110129.2:n.2628dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Fanconi anemia (FA)
Synonyms:: Fanconi pancytopenia; Fanconi's anemia
Identifiers:: MONDO: MONDO:0019391; MeSH: D005199; MedGen: C0015625; Orphanet: 84; OMIM: PS227650

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001543985	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11091222, 28492532
SCV001832569	Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001543985

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 6, 2023)

germline

clinical testing

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

SCV001832569

Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
South Asian	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients.

Tamary H, Bar-Yam R, Shalmon L, Rachavi G, Krostichevsky M, Elhasid R, Barak Y, Kapelushnik J, Yaniv I, Auerbach AD, Zaizov R.

Br J Haematol. 2000 Oct;111(1):338-43. Erratum in: Br J Haematol 2001 Mar;112(3):829.

PubMed [citation]

PMID:: 11091222

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001543985.4

#	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 creates a premature translational stop signal (p.Ile1396Aspfs*29) in the FANCA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the FANCA protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1045251). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the FANCA protein in which other variant(s) (p.Asp1427Thrfs*6) have been determined to be pathogenic (PMID: 11091222). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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

From Dept. of Cytogenetics, ICMR- National Institute of Immunohaematology, SCV001832569.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	South Asian	3	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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