rs7354779

Positions:

• chr21-44250887-T-C

Variant summary

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

The NM_175867.3(DNMT3L):​c.832A>G​(p.Arg278Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency: Genomes: not found (cov: 0)
• Consequence: DNMT3L NM_175867.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57

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]

DNMT3L-AS1 (HGNC:40189): (DNMT3L antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009047687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3L	NM_175867.3	c.832A>G	p.Arg278Gly	missense_variant	10/12	ENST00000628202.3
DNMT3L-AS1	NR_135514.1	n.75T>C		non_coding_transcript_exon_variant	1/2
DNMT3L	NM_013369.4	c.832A>G	p.Arg278Gly	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3L	ENST00000628202.3	c.832A>G	p.Arg278Gly	missense_variant	10/12	1	NM_175867.3	A2
DNMT3L-AS1	ENST00000442785.1	n.75T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.210 AC: 52546 AN: 249668 Hom.: 6477 AF XY: 0.212 AC XY: 28707 AN XY: 135290

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.0459

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.221

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.256 Hom.: 12248

TwinsUK AF: 0.260 AC: 963

ALSPAC AF: 0.273 AC: 1053

ESP6500AA AF: 0.239 AC: 1051

ESP6500EA AF: 0.263 AC: 2265

ExAC AF: 0.214 AC: 25983

Asia WGS AF: 0.115 AC: 401 AN: 3478

EpiCase AF: 0.258

EpiControl AF: 0.265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.64
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.73	T;T;T
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-6.1	D;.;D
REVEL	Benign	0.13
Sift	Uncertain	0.025	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.52	P;P;.
Vest4		0.13
MPC		0.36
ClinPred		0.037	T
GERP RS		0.12
Varity_R		0.47
gMVP		0.61

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: rs7354779; hg19: chr21-45670770; COSMIC: COSV54263126;