rs11695471

Variant names:

• chr2-25234839-T-A
• rs11695471
• NM_022552.5:c.2598-419A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-25234839-T-A
• chr2-25234839-T-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.2598-419A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,038 control chromosomes in the GnomAD database, including 4,618 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 0.22 (4618 hom., cov: 31)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 18 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022552.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	NM_022552.5	MANE Select	c.2598-419A>T		intron	N/A	NP_072046.2
	DNMT3A	NM_175629.2		c.2598-419A>T		intron	N/A	NP_783328.1
	DNMT3A	NM_001320893.1		c.2142-419A>T		intron	N/A	NP_001307822.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.2598-419A>T		intron	N/A	ENSP00000324375.5
	DNMT3A	ENST00000264709.7	TSL:1	c.2598-419A>T		intron	N/A	ENSP00000264709.3
	DNMT3A	ENST00000380746.8	TSL:1	c.2031-419A>T		intron	N/A	ENSP00000370122.4

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33512 AN: 151920 Hom.: 4619 Cov.: 31

Gnomad AFR AF: 0.0568

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.0877

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.230

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

GnomAD4 genome AF: 0.220 AC: 33505 AN: 152038 Hom.: 4618 Cov.: 31 AF XY: 0.215 AC XY: 15996 AN XY: 74300

African (AFR) AF: 0.0567 AC: 2351 AN: 41472

American (AMR) AF: 0.164 AC: 2500 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 981 AN: 3470

East Asian (EAS) AF: 0.0881 AC: 456 AN: 5176

South Asian (SAS) AF: 0.243 AC: 1166 AN: 4808

European-Finnish (FIN) AF: 0.305 AC: 3220 AN: 10570

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21934 AN: 67958

Other (OTH) AF: 0.227 AC: 479 AN: 2110

Alfa AF: 0.257 Hom.: 783

Bravo AF: 0.200

Asia WGS AF: 0.137 AC: 480 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.61
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11695471; hg19: chr2-25457708;