rs121908944

Positions:

• chr20-32805343-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The ENST00000328111.6(DNMT3B):​c.2237T>G​(p.Val746Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V746M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNMT3B ENST00000328111.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.88

Genes affected

DNMT3B (HGNC:2979): (DNA methyltransferase 3 beta) CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase which is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes primarily to the nucleus and its expression is developmentally regulated. Mutations in this gene cause the immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. Eight alternatively spliced transcript variants have been described. The full length sequences of variants 4 and 5 have not been determined. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain SAM-dependent MTase C5-type (size 278) in uniprot entity DNM3B_HUMAN there are 46 pathogenic changes around while only 2 benign (96%) in ENST00000328111.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNMT3B. . Gene score misZ 1.5 (greater than the threshold 3.09). Trascript score misZ 3.3234 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency-centromeric instability-facial anomalies syndrome, immunodeficiency-centromeric instability-facial anomalies syndrome 1.
• PP5: Variant 20-32805343-T-G is Pathogenic according to our data. Variant chr20-32805343-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 6742.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3B	NM_006892.4	c.2237T>G	p.Val746Gly	missense_variant	21/23	ENST00000328111.6	NP_008823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3B	ENST00000328111.6	c.2237T>G	p.Val746Gly	missense_variant	21/23	1	NM_006892.4	ENSP00000328547	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 11, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.96	D;P;P
Vest4		0.49
MutPred		0.65		Gain of disorder (P = 0.0081);.;.;
MVP		0.90
MPC		2.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908944; hg19: chr20-31393149;