2-25300227-T-G

Variant names:

• chr2-25300227-T-G
• rs143730975
• NM_022552.5:c.89A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022552.5(DNMT3A):​c.89A>C​(p.Glu30Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00274 in 1,608,508 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E30G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (11 hom.)
• Consequence: DNMT3A NM_022552.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 4.37
• Publications: 22 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 (MetaRNN=0.0073841214).
• BP6: Variant 2-25300227-T-G is Benign according to our data. Variant chr2-25300227-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00326 (496/152264) while in subpopulation NFE AF = 0.00291 (198/68012). AF 95% confidence interval is 0.00258. There are 8 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 496 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	NM_022552.5	MANE Select	c.89A>C	p.Glu30Ala	missense	Exon 3 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.89A>C	p.Glu30Ala	missense	Exon 3 of 23	NP_783328.1
	DNMT3A	NM_001320892.2		c.89A>C	p.Glu30Ala	missense	Exon 3 of 4	NP_001307821.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.89A>C	p.Glu30Ala	missense	Exon 3 of 23	ENSP00000324375.5
	DNMT3A	ENST00000264709.7	TSL:1	c.89A>C	p.Glu30Ala	missense	Exon 3 of 23	ENSP00000264709.3
	DNMT3A	ENST00000406659.3	TSL:1	c.89A>C	p.Glu30Ala	missense	Exon 3 of 4	ENSP00000384852.3

Frequencies

GnomAD3 genomes AF: 0.00326 AC: 496 AN: 152146 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00326 AC: 801 AN: 245602 AF XY: 0.00328

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.00292

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00269 AC: 3912 AN: 1456244 Hom.: 11 Cov.: 31 AF XY: 0.00259 AC XY: 1879 AN XY: 724710

African (AFR) AF: 0.000299 AC: 10 AN: 33472

American (AMR) AF: 0.00165 AC: 74 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86254

European-Finnish (FIN) AF: 0.0187 AC: 895 AN: 47934

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.00241 AC: 2681 AN: 1111934

Other (OTH) AF: 0.00250 AC: 151 AN: 60360

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152264 Hom.: 8 Cov.: 31 AF XY: 0.00411 AC XY: 306 AN XY: 74448

African (AFR) AF: 0.000626 AC: 26 AN: 41554

American (AMR) AF: 0.00157 AC: 24 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0215 AC: 228 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00291 AC: 198 AN: 68012

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00239 Hom.: 2

Bravo AF: 0.00161

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00292 AC: 354

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Tatton-Brown-Rahman overgrowth syndrome (2)
-	-	1	DNMT3A-related disorder (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0074	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	0.69	N
PhyloP100		4.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.24	N
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.063	T
Polyphen		0.88	P
Vest4		0.39
MVP		0.99
MPC		1.3
ClinPred		0.038	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.14
Mutation Taster		=91/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs143730975; hg19: chr2-25523096; COSMIC: COSV53049288;