rs116609083

Variant names:

• chr2-25248091-G-A
• rs116609083
• NM_022552.5:c.801C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_022552.5(DNMT3A):​c.801C>T​(p.Ser267Ser) 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S267S) has been classified as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.93
• Publications: 2 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 -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/Likely_benign. ClinVar VariationId is 541938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 366 AD gene.

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.801C>T	p.Ser267Ser	synonymous	Exon 7 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.801C>T	p.Ser267Ser	synonymous	Exon 7 of 23	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320893.1		c.345C>T	p.Ser115Ser	synonymous	Exon 2 of 18	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.801C>T	p.Ser267Ser	synonymous	Exon 7 of 23	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.801C>T	p.Ser267Ser	synonymous	Exon 7 of 23	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380746.8	TSL:1	c.234C>T	p.Ser78Ser	synonymous	Exon 3 of 19	ENSP00000370122.4	Q9Y6K1-2

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

GnomAD2 exomes AF: 0.00249 AC: 620 AN: 248854 AF XY: 0.00239

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 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

African (AFR) AF: 0.000658 AC: 22 AN: 33436

American (AMR) AF: 0.00504 AC: 225 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26124

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53354

Middle Eastern (MID) AF: 0.000784 AC: 4 AN: 5104

European-Non Finnish (NFE) AF: 0.00304 AC: 3381 AN: 1111974

Other (OTH) AF: 0.00317 AC: 191 AN: 60304

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

African (AFR) AF: 0.000602 AC: 25 AN: 41556

American (AMR) AF: 0.00673 AC: 103 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68006

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Inborn genetic diseases (1)
-	-	1	Tatton-Brown-Rahman overgrowth syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.17
DANN	Benign	0.70
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism

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: rs116609083; hg19: chr2-25470960;