rs116609083

Positions:

• chr2-25248091-G-A
• chr2-25248091-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022552.5(DNMT3A):​c.801C>T​(p.Ser267=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,613,112 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (11 hom.)
• Consequence: DNMT3A NM_022552.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.93

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-25248091-G-A is Benign according to our data. Variant chr2-25248091-G-A is described in ClinVar as [Benign]. Clinvar id is 541938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-25248091-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0024 (366/152254) while in subpopulation AMR AF= 0.00673 (103/15296). AF 95% confidence interval is 0.00568. There are 1 homozygotes in gnomad4. There are 174 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.801C>T	p.Ser267=	synonymous_variant	7/23	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.801C>T	p.Ser267=	synonymous_variant	7/23	1	NM_022552.5	ENSP00000324375	P3

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152138 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00249 AC: 620 AN: 248854 Hom.: 2 AF XY: 0.00239 AC XY: 322 AN XY: 134714

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00574

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00283

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00271 AC: 3954 AN: 1460858 Hom.: 11 Cov.: 32 AF XY: 0.00257 AC XY: 1866 AN XY: 726664

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00504

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.000781

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00304

Gnomad4 OTH exome AF: 0.00317

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00234 AC XY: 174 AN XY: 74436

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00271 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	DNMT3A: BP4, BP7, BS1, BS2 -

Tatton-Brown-Rahman overgrowth syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.17
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs116609083; hg19: chr2-25470960;