rs7581217

Variant names:

• chr2-25302075-T-C
• rs7581217
• NM_022552.5:c.73-1832A>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.73-1832A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 151,956 control chromosomes in the GnomAD database, including 29,594 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 0.62 (29594 hom., cov: 32)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.942
• Publications: 13 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.73-1832A>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.73-1832A>G		intron_variant	Intron 2 of 22	1	NM_022552.5	ENSP00000324375.5
DNMT3A	ENST00000264709.7	c.73-1832A>G		intron_variant	Intron 2 of 22	1		ENSP00000264709.3
DNMT3A	ENST00000406659.3	c.73-1832A>G		intron_variant	Intron 2 of 3	1		ENSP00000384852.3
DNMT3A	ENST00000380756.7	n.73-1832A>G		intron_variant	Intron 2 of 23	1		ENSP00000370132.3

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94185 AN: 151836 Hom.: 29559 Cov.: 32

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.620 AC: 94270 AN: 151956 Hom.: 29594 Cov.: 32 AF XY: 0.617 AC XY: 45829 AN XY: 74250

African (AFR) AF: 0.603 AC: 24959 AN: 41408

American (AMR) AF: 0.480 AC: 7336 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2198 AN: 3470

East Asian (EAS) AF: 0.577 AC: 2968 AN: 5142

South Asian (SAS) AF: 0.724 AC: 3491 AN: 4822

European-Finnish (FIN) AF: 0.639 AC: 6741 AN: 10544

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.655 AC: 44507 AN: 67970

Other (OTH) AF: 0.595 AC: 1260 AN: 2116

Alfa AF: 0.639 Hom.: 54523

Bravo AF: 0.604

Asia WGS AF: 0.599 AC: 2083 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.55
DANN	Benign	0.43
PhyloP100		-0.94
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: rs7581217; hg19: chr2-25524944;