2-25260014-T-C

Variant names:

• chr2-25260014-T-C
• rs7594432
• NM_022552.5:c.640-11762A>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.640-11762A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 152,032 control chromosomes in the GnomAD database, including 17,455 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 0.47 (17455 hom., cov: 32)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• Publications: 16 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.640-11762A>G		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.640-11762A>G		intron_variant	Intron 6 of 22	1	NM_022552.5	ENSP00000324375.5
DNMT3A	ENST00000264709.7	c.640-11762A>G		intron_variant	Intron 6 of 22	1		ENSP00000264709.3
DNMT3A	ENST00000380756.7	n.640-11762A>G		intron_variant	Intron 6 of 23	1		ENSP00000370132.3

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72080 AN: 151914 Hom.: 17429 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.449

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

GnomAD4 genome AF: 0.475 AC: 72149 AN: 152032 Hom.: 17455 Cov.: 32 AF XY: 0.479 AC XY: 35630 AN XY: 74312

African (AFR) AF: 0.522 AC: 21652 AN: 41440

American (AMR) AF: 0.564 AC: 8624 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1363 AN: 3470

East Asian (EAS) AF: 0.519 AC: 2678 AN: 5164

South Asian (SAS) AF: 0.365 AC: 1756 AN: 4812

European-Finnish (FIN) AF: 0.515 AC: 5441 AN: 10556

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29233 AN: 67992

Other (OTH) AF: 0.454 AC: 959 AN: 2114

Alfa AF: 0.442 Hom.: 67529

Bravo AF: 0.486

Asia WGS AF: 0.485 AC: 1686 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.021
DANN	Benign	0.39
PhyloP100		-1.4
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: rs7594432; hg19: chr2-25482883;