2-25262866-C-T

Variant names:

• chr2-25262866-C-T
• rs11887120
• NM_022552.5:c.639+12075G>A

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+12075G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 152,038 control chromosomes in the GnomAD database, including 15,706 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 0.45 (15706 hom., cov: 32)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.409
• Publications: 24 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.639+12075G>A		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+12075G>A		intron_variant	Intron 6 of 22	1	NM_022552.5	ENSP00000324375.5
DNMT3A	ENST00000264709.7	c.639+12075G>A		intron_variant	Intron 6 of 22	1		ENSP00000264709.3
DNMT3A	ENST00000380756.7	n.639+12075G>A		intron_variant	Intron 6 of 23	1		ENSP00000370132.3

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68521 AN: 151920 Hom.: 15674 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.353

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.451 AC: 68606 AN: 152038 Hom.: 15706 Cov.: 32 AF XY: 0.454 AC XY: 33738 AN XY: 74322

African (AFR) AF: 0.501 AC: 20761 AN: 41452

American (AMR) AF: 0.525 AC: 8018 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1284 AN: 3470

East Asian (EAS) AF: 0.499 AC: 2583 AN: 5172

South Asian (SAS) AF: 0.367 AC: 1768 AN: 4824

European-Finnish (FIN) AF: 0.449 AC: 4742 AN: 10562

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

European-Non Finnish (NFE) AF: 0.413 AC: 28096 AN: 67972

Other (OTH) AF: 0.435 AC: 918 AN: 2110

Alfa AF: 0.420 Hom.: 26688

Bravo AF: 0.462

Asia WGS AF: 0.463 AC: 1608 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.5
DANN	Benign	0.44
PhyloP100		-0.41
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: rs11887120; hg19: chr2-25485735;