rs370534287

chr2-25313903-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022552.5(DNMT3A):c.72+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,549,148 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.42

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-25313903-C-T is Benign according to our data. Variant chr2-25313903-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 541939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-25313903-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00109 (1523/1396816) while in subpopulation NFE AF= 0.00119 (1285/1078802). AF 95% confidence interval is 0.00114. There are 2 homozygotes in gnomad4_exome. There are 714 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 94 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT3A	NM_022552.5	c.72+10G>A		intron_variant		ENST00000321117.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT3A	ENST00000321117.10	c.72+10G>A		intron_variant		1	NM_022552.5	P3
DNMT3A	ENST00000264709.7	c.72+10G>A		intron_variant		1		P3
DNMT3A	ENST00000406659.3	c.72+10G>A		intron_variant		1
DNMT3A	ENST00000380756.7	c.72+10G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00101 AC: 155 AN: 154038 Hom.: 1 AF XY: 0.00108 AC XY: 88 AN XY: 81358

Gnomad AFR exome AF: 0.000230

Gnomad AMR exome AF: 0.000566

Gnomad ASJ exome AF: 0.00683

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000878

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00109 AC: 1523 AN: 1396816 Hom.: 2 Cov.: 30 AF XY: 0.00104 AC XY: 714 AN XY: 688980

Gnomad4 AFR exome AF: 0.0000634

Gnomad4 AMR exome AF: 0.000420

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.0000615

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152332 Hom.: 1 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74486

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.000620

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 02, 2018

- -

DNMT3A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Tatton-Brown-Rahman overgrowth syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.019
Dann	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs370534287; hg19: chr2-25536772;