rs13428812

Variant names:

• chr2-25269598-A-G
• rs13428812
• NM_022552.5:c.639+5343T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-25269598-A-G
• chr2-25269598-A-T

Variant summary

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

The NM_022552.5(DNMT3A):​c.639+5343T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 151,960 control chromosomes in the GnomAD database, including 7,204 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 0.31 (7204 hom., cov: 31)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.537
• Publications: 55 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.639+5343T>C		intron_variant	Intron 6 of 22	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.639+5343T>C		intron_variant	Intron 6 of 22	1	NM_022552.5	ENSP00000324375.5
DNMT3A	ENST00000264709.7	c.639+5343T>C		intron_variant	Intron 6 of 22	1		ENSP00000264709.3
DNMT3A	ENST00000380756.7	n.639+5343T>C		intron_variant	Intron 6 of 23	1		ENSP00000370132.3

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46437 AN: 151842 Hom.: 7206 Cov.: 31

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.328

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

GnomAD4 genome AF: 0.306 AC: 46442 AN: 151960 Hom.: 7204 Cov.: 31 AF XY: 0.306 AC XY: 22713 AN XY: 74290

African (AFR) AF: 0.315 AC: 13049 AN: 41422

American (AMR) AF: 0.265 AC: 4040 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1133 AN: 3468

East Asian (EAS) AF: 0.243 AC: 1254 AN: 5170

South Asian (SAS) AF: 0.234 AC: 1125 AN: 4812

European-Finnish (FIN) AF: 0.306 AC: 3243 AN: 10596

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21524 AN: 67916

Other (OTH) AF: 0.325 AC: 684 AN: 2104

Alfa AF: 0.309 Hom.: 23025

Bravo AF: 0.304

Asia WGS AF: 0.213 AC: 743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.4
DANN	Benign	0.83
PhyloP100		0.54
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: rs13428812; hg19: chr2-25492467;