rs734693

Variant names:

• chr2-25241002-C-T
• rs734693
• NM_022552.5:c.2083-272G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022552.5(DNMT3A):​c.2083-272G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 151,964 control chromosomes in the GnomAD database, including 33,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.65 (33295 hom., cov: 31)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.110
• Publications: 17 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: Orphanet, Illumina, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Heyn-Sproul-Jackson syndrome

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-25241002-C-T is Benign according to our data. Variant chr2-25241002-C-T is described in ClinVar as Benign. ClinVar VariationId is 1183786.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.74 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.2083-272G>A		intron	N/A	NP_072046.2
	DNMT3A	NM_175629.2		c.2083-272G>A		intron	N/A	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320893.1		c.1627-272G>A		intron	N/A	NP_001307822.1	Q9Y6K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.2083-272G>A		intron	N/A	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.2083-272G>A		intron	N/A	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380746.8	TSL:1	c.1516-272G>A		intron	N/A	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98310 AN: 151846 Hom.: 33275 Cov.: 31

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.715

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.790

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.644

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

GnomAD4 genome AF: 0.647 AC: 98378 AN: 151964 Hom.: 33295 Cov.: 31 AF XY: 0.644 AC XY: 47856 AN XY: 74280

African (AFR) AF: 0.488 AC: 20225 AN: 41418

American (AMR) AF: 0.678 AC: 10359 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2268 AN: 3470

East Asian (EAS) AF: 0.332 AC: 1709 AN: 5152

South Asian (SAS) AF: 0.551 AC: 2657 AN: 4822

European-Finnish (FIN) AF: 0.790 AC: 8360 AN: 10580

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.745 AC: 50607 AN: 67934

Other (OTH) AF: 0.642 AC: 1352 AN: 2106

Alfa AF: 0.709 Hom.: 21114

Bravo AF: 0.632

Asia WGS AF: 0.441 AC: 1536 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.26
DANN	Benign	0.47
PhyloP100		0.11
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: rs734693; hg19: chr2-25463871;