rs7575625

Variant names:

• chr2-25326033-A-G
• rs7575625
• NM_022552.5:c.-177-11872T>C

Variant summary

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

The NM_022552.5(DNMT3A):​c.-177-11872T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 151,714 control chromosomes in the GnomAD database, including 13,563 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 0.42 (13563 hom., cov: 31)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 14 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.-177-11872T>C		intron_variant	Intron 1 of 22	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.-177-11872T>C		intron_variant	Intron 1 of 22	1	NM_022552.5	ENSP00000324375.5
DNMT3A	ENST00000264709.7	c.-177-11872T>C		intron_variant	Intron 1 of 22	1		ENSP00000264709.3
DNMT3A	ENST00000406659.3	c.-177-11872T>C		intron_variant	Intron 1 of 3	1		ENSP00000384852.3
DNMT3A	ENST00000380756.7	n.-177-11872T>C		intron_variant	Intron 1 of 23	1		ENSP00000370132.3

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63498 AN: 151596 Hom.: 13555 Cov.: 31

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.432

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

GnomAD4 genome AF: 0.419 AC: 63526 AN: 151714 Hom.: 13563 Cov.: 31 AF XY: 0.418 AC XY: 30953 AN XY: 74116

African (AFR) AF: 0.444 AC: 18349 AN: 41320

American (AMR) AF: 0.359 AC: 5471 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1657 AN: 3466

East Asian (EAS) AF: 0.227 AC: 1172 AN: 5158

South Asian (SAS) AF: 0.258 AC: 1239 AN: 4806

European-Finnish (FIN) AF: 0.500 AC: 5244 AN: 10480

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 29023 AN: 67922

Other (OTH) AF: 0.426 AC: 895 AN: 2102

Alfa AF: 0.422 Hom.: 43484

Bravo AF: 0.413

Asia WGS AF: 0.222 AC: 775 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.27
PhyloP100		0.0
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: rs7575625; hg19: chr2-25548902;