chr2-25295601-C-A

Variant names:

• chr2-25295601-C-A
• rs13401241
• NM_022552.5:c.177+4538G>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.177+4538G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 152,090 control chromosomes in the GnomAD database, including 18,605 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 0.49 (18605 hom., cov: 33)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690
• Publications: 12 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.177+4538G>T		intron_variant	Intron 3 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+4538G>T		intron_variant	Intron 3 of 22	1	NM_022552.5	ENSP00000324375.5
DNMT3A	ENST00000264709.7	c.177+4538G>T		intron_variant	Intron 3 of 22	1		ENSP00000264709.3
DNMT3A	ENST00000406659.3	c.177+4538G>T		intron_variant	Intron 3 of 3	1		ENSP00000384852.3
DNMT3A	ENST00000380756.7	n.177+4538G>T		intron_variant	Intron 3 of 23	1		ENSP00000370132.3

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74216 AN: 151972 Hom.: 18590 Cov.: 33

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.535

Gnomad OTH AF: 0.492

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

GnomAD4 genome AF: 0.488 AC: 74259 AN: 152090 Hom.: 18605 Cov.: 33 AF XY: 0.487 AC XY: 36182 AN XY: 74348

African (AFR) AF: 0.465 AC: 19275 AN: 41496

American (AMR) AF: 0.381 AC: 5827 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1983 AN: 3470

East Asian (EAS) AF: 0.289 AC: 1496 AN: 5174

South Asian (SAS) AF: 0.385 AC: 1853 AN: 4816

European-Finnish (FIN) AF: 0.553 AC: 5842 AN: 10560

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.535 AC: 36365 AN: 67976

Other (OTH) AF: 0.486 AC: 1029 AN: 2116

Alfa AF: 0.520 Hom.: 80505

Bravo AF: 0.475

Asia WGS AF: 0.335 AC: 1169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.3
DANN	Benign	0.47
PhyloP100		-0.069
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: rs13401241; hg19: chr2-25518470;