21-44249054-C-T

Variant names:

• chr21-44249054-C-T
• rs766968732
• NM_175867.3:c.967G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_175867.3(DNMT3L):​c.967G>A​(p.Val323Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: DNMT3L NM_175867.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.858

Genes affected

DNMT3L (HGNC:2980): (DNA methyltransferase 3 like) 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 nuclear protein with similarity to DNA methyltransferases, but is not thought to function as a DNA methyltransferase as it does not contain the amino acid residues necessary for methyltransferase activity. However, it does stimulate de novo methylation by DNA cytosine methyltransferase 3 alpha and is thought to be required for the establishment of maternal genomic imprints. This protein also mediates transcriptional repression through interaction with histone deacetylase 1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.967G>A	p.Val323Met	missense_variant	Exon 11 of 12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.967G>A	p.Val323Met	missense_variant	Exon 11 of 12		NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.967G>A	p.Val323Met	missense_variant	Exon 11 of 12	1	NM_175867.3	ENSP00000486001.1
DNMT3L	ENST00000270172.7	c.967G>A	p.Val323Met	missense_variant	Exon 11 of 12	1		ENSP00000270172.3
DNMT3L	ENST00000436357.5	n.351G>A		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247624 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 134050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000447 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.967G>A (p.V323M) alteration is located in exon 11 (coding exon 10) of the DNMT3L gene. This alteration results from a G to A substitution at nucleotide position 967, causing the valine (V) at amino acid position 323 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.25	N;.
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.40		Gain of MoRF binding (P = 0.097);Gain of MoRF binding (P = 0.097);
MVP		0.35
MPC		0.62
ClinPred		0.58	D
GERP RS		3.0
Varity_R		0.20
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs766968732; hg19: chr21-45668937;