chr21-44249081-C-T

Position:

• chr21-44249081-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_175867.3(DNMT3L):​c.940G>A​(p.Gly314Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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: 0.276

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027355582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.940G>A	p.Gly314Ser	missense_variant	11/12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.940G>A	p.Gly314Ser	missense_variant	11/12		NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.940G>A	p.Gly314Ser	missense_variant	11/12	1	NM_175867.3	ENSP00000486001	A2
DNMT3L	ENST00000270172.7	c.940G>A	p.Gly314Ser	missense_variant	11/12	1		ENSP00000270172	P4
DNMT3L	ENST00000436357.5	n.324G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000153 AC: 38 AN: 248212 Hom.: 0 AF XY: 0.000127 AC XY: 17 AN XY: 134358

Gnomad AFR exome AF: 0.000376

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000332

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000974 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.940G>A (p.G314S) 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 940, causing the glycine (G) at amino acid position 314 to be replaced by a serine (S). 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	Benign	0.089
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.88	N;.
REVEL	Benign	0.15
Sift	Uncertain	0.025	D;.
Sift4G	Uncertain	0.032	D;D
Polyphen		1.0	D;D
Vest4		0.35
MVP		0.45
MPC		0.16
ClinPred		0.021	T
GERP RS		3.0
Varity_R		0.27
gMVP		0.50

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: rs145523482; hg19: chr21-45668964;