NM_006892.4(DNMT3B):c.2296G>C (p.Ala766Pro) AND Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 22, 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:: RCV003593402.2

Allele description [Variation Report for NM_006892.4(DNMT3B):c.2296G>C (p.Ala766Pro)]

NM_006892.4(DNMT3B):c.2296G>C (p.Ala766Pro)

Gene:

DNMT3B:DNA methyltransferase 3 beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q11.21

Genomic location:

Preferred name:

NM_006892.4(DNMT3B):c.2296G>C (p.Ala766Pro)

HGVS:

NC_000020.11:g.32805402G>C
NG_007290.1:g.48018G>C
NM_001207055.2:c.2046-2360G>C
NM_001207056.2:c.1944-2360G>C
NM_001424351.1:c.2296G>C
NM_001424352.1:c.2170G>C
NM_001424353.1:c.2236G>C
NM_001424354.1:c.2110G>C
NM_001424355.1:c.2232-2360G>C
NM_001424356.1:c.2170G>C
NM_001424357.1:c.2110G>C
NM_001424358.1:c.2106-2360G>C
NM_001424359.1:c.2208-2360G>C
NM_001424360.1:c.2082-2360G>C
NM_006892.4:c.2296G>CMANE SELECT
NM_175848.2:c.2236G>C
NM_175849.2:c.2172-2360G>C
NM_175850.3:c.2272G>C
NP_001411280.1:p.Ala766Pro
NP_001411281.1:p.Ala724Pro
NP_001411282.1:p.Ala746Pro
NP_001411283.1:p.Ala704Pro
NP_001411285.1:p.Ala724Pro
NP_001411286.1:p.Ala704Pro
NP_008823.1:p.Ala766Pro
NP_008823.1:p.Ala766Pro
NP_787044.1:p.Ala746Pro
NP_787046.1:p.Ala758Pro
LRG_56t1:c.2296G>C
LRG_56:g.48018G>C
LRG_56p1:p.Ala766Pro
NC_000020.10:g.31393208G>C
NM_006892.3:c.2296G>C

Protein change:

A704P

Molecular consequence:

NM_001207055.2:c.2046-2360G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001207056.2:c.1944-2360G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001424355.1:c.2232-2360G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001424358.1:c.2106-2360G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001424359.1:c.2208-2360G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001424360.1:c.2082-2360G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_175849.2:c.2172-2360G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001424351.1:c.2296G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001424352.1:c.2170G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001424353.1:c.2236G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001424354.1:c.2110G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001424356.1:c.2170G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001424357.1:c.2110G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006892.4:c.2296G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_175848.2:c.2236G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_175850.3:c.2272G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (ICF1)
Synonyms:: ICF syndrome; Immunodeficiency syndrome, variable; Centromeric instability, immunodeficiency syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0000133; MedGen: C0398788; OMIM: PS242860

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004298050	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 22, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11102980, 17893117, 16543361, 21549127, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004298050

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 22, 2023)

germline

clinical testing

PubMed (5)
[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

Citations

PubMed

Genetic variation in ICF syndrome: evidence for genetic heterogeneity.

Wijmenga C, Hansen RS, Gimelli G, Björck EJ, Davies EG, Valentine D, Belohradsky BH, van Dongen JJ, Smeets DF, van den Heuvel LP, Luyten JA, Strengman E, Weemaes C, Pearson PL.

Hum Mutat. 2000 Dec;16(6):509-17. Review.

PubMed [citation]

PMID:: 11102980

Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).

Hagleitner MM, Lankester A, Maraschio P, Hultén M, Fryns JP, Schuetz C, Gimelli G, Davies EG, Gennery A, Belohradsky BH, de Groot R, Gerritsen EJ, Mattina T, Howard PJ, Fasth A, Reisli I, Furthner D, Slatter MA, Cant AJ, Cazzola G, van Dijken PJ, van Deuren M, et al.

J Med Genet. 2008 Feb;45(2):93-9. Epub 2007 Sep 24.

PubMed [citation]

PMID:: 17893117

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298050.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 766 of the DNMT3B protein (p.Ala766Pro). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of DNMT3B-related conditions and/or ICF syndrome (PMID: 11102980, 17893117; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 expected to disrupt DNMT3B protein function. Experimental studies have shown that this missense change affects DNMT3B function (PMID: 16543361, 21549127). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Sep 29, 2024

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