rs2289195

Variant names:

• chr2-25240614-G-A
• rs2289195
• NM_022552.5:c.2173+26C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022552.5(DNMT3A):​c.2173+26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,611,360 control chromosomes in the GnomAD database, including 135,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13193 hom., cov: 33)
  • Exomes 𝑓: 0.41 (122217 hom.)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.130
• Publications: 45 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-25240614-G-A is Benign according to our data. Variant chr2-25240614-G-A is described in ClinVar as Benign. ClinVar VariationId is 1235844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.2173+26C>T		intron_variant	Intron 18 of 22	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.2173+26C>T		intron_variant	Intron 18 of 22	1	NM_022552.5	ENSP00000324375.5

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62386 AN: 151982 Hom.: 13174 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.402

GnomAD2 exomes AF: 0.411 AC: 102680 AN: 249872 AF XY: 0.403

Gnomad AFR exome AF: 0.368

Gnomad AMR exome AF: 0.549

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.242

Gnomad FIN exome AF: 0.471

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.406 AC: 592241 AN: 1459260 Hom.: 122217 Cov.: 35 AF XY: 0.403 AC XY: 292278 AN XY: 725662

African (AFR) AF: 0.370 AC: 12380 AN: 33426

American (AMR) AF: 0.542 AC: 24118 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10486 AN: 26058

East Asian (EAS) AF: 0.236 AC: 9358 AN: 39628

South Asian (SAS) AF: 0.312 AC: 26843 AN: 86042

European-Finnish (FIN) AF: 0.472 AC: 25172 AN: 53380

Middle Eastern (MID) AF: 0.404 AC: 2324 AN: 5756

European-Non Finnish (NFE) AF: 0.412 AC: 457538 AN: 1110248

Other (OTH) AF: 0.399 AC: 24022 AN: 60260

GnomAD4 genome AF: 0.411 AC: 62441 AN: 152100 Hom.: 13193 Cov.: 33 AF XY: 0.413 AC XY: 30727 AN XY: 74362

African (AFR) AF: 0.373 AC: 15472 AN: 41482

American (AMR) AF: 0.511 AC: 7805 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1345 AN: 3468

East Asian (EAS) AF: 0.246 AC: 1273 AN: 5180

South Asian (SAS) AF: 0.318 AC: 1533 AN: 4820

European-Finnish (FIN) AF: 0.483 AC: 5106 AN: 10580

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28628 AN: 67964

Other (OTH) AF: 0.403 AC: 851 AN: 2112

Alfa AF: 0.416 Hom.: 24564

Bravo AF: 0.414

Asia WGS AF: 0.304 AC: 1058 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2289195; hg19: chr2-25463483; COSMIC: COSV53044122; COSMIC: COSV53044122;