rs121908947

Positions:

• chr20-32789007-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_006892.4(DNMT3B):​c.808T>C​(p.Ser270Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S270S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT3B NM_006892.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.98

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 8 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 20-32789007-T-C is Pathogenic according to our data. Variant chr20-32789007-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6745.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-32789007-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3B	NM_006892.4	c.808T>C	p.Ser270Pro	missense_variant	7/23	ENST00000328111.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3B	ENST00000328111.6	c.808T>C	p.Ser270Pro	missense_variant	7/23	1	NM_006892.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Sep 15, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;D
Vest4		0.99
MutPred		0.81		Loss of MoRF binding (P = 0.0675);Loss of MoRF binding (P = 0.0675);Loss of MoRF binding (P = 0.0675);.;.;.;
MVP		0.95
MPC		0.82
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121908947; hg19: chr20-31376813;