rs749131

Variant names:

• chr2-25306755-A-C
• rs749131
• NM_022552.5:c.73-6512T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022552.5(DNMT3A):​c.73-6512T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,022 control chromosomes in the GnomAD database, including 21,547 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (21547 hom., cov: 32)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.668
• Publications: 17 publications found

Genes affected

DNMT3A (HGNC:2978): (DNA methyltransferase 3 alpha) 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 that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016]

DNMT3A Gene-Disease associations (from GenCC):

• Tatton-Brown-Rahman overgrowth syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Heyn-Sproul-Jackson syndrome

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.73-6512T>G		intron_variant	Intron 2 of 22	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.73-6512T>G		intron_variant	Intron 2 of 22	1	NM_022552.5	ENSP00000324375.5
DNMT3A	ENST00000264709.7	c.73-6512T>G		intron_variant	Intron 2 of 22	1		ENSP00000264709.3
DNMT3A	ENST00000406659.3	c.73-6512T>G		intron_variant	Intron 2 of 3	1		ENSP00000384852.3
DNMT3A	ENST00000380756.7	n.73-6512T>G		intron_variant	Intron 2 of 23	1		ENSP00000370132.3

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80372 AN: 151904 Hom.: 21526 Cov.: 32

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.524

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.529 AC: 80431 AN: 152022 Hom.: 21547 Cov.: 32 AF XY: 0.524 AC XY: 38903 AN XY: 74312

African (AFR) AF: 0.568 AC: 23528 AN: 41436

American (AMR) AF: 0.406 AC: 6207 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2063 AN: 3468

East Asian (EAS) AF: 0.329 AC: 1704 AN: 5174

South Asian (SAS) AF: 0.381 AC: 1840 AN: 4826

European-Finnish (FIN) AF: 0.577 AC: 6096 AN: 10564

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37274 AN: 67966

Other (OTH) AF: 0.518 AC: 1094 AN: 2110

Alfa AF: 0.525 Hom.: 3693

Bravo AF: 0.519

Asia WGS AF: 0.350 AC: 1220 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.72
DANN	Benign	0.65
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs749131; hg19: chr2-25529624;