Genetic Variant NM_022552.5:c.2597+30G>A (chr2-25235677-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022552.5(DNMT3A):c.2597+30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,579,922 control chromosomes in the GnomAD database, including 246,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 18032 hom., cov: 32)

Exomes 𝑓: 0.56 ( 228680 hom. )

Consequence

DNMT3A
NM_022552.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.83

Publications

33 publications found

Variant links:

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

DNMT3A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 2-25235677-C-T is Benign according to our data. Variant chr2-25235677-C-T is described in ClinVar as Benign. ClinVar VariationId is 1220822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DNMT3A	NM_022552.5	MANE Select	c.2597+30G>A	intron	N/A	NP_072046.2
DNMT3A	NM_175629.2		c.2597+30G>A	intron	N/A	NP_783328.1	Q9Y6K1-1
DNMT3A	NM_001320893.1		c.2141+30G>A	intron	N/A	NP_001307822.1	Q9Y6K1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.2597+30G>A	intron	N/A	ENSP00000324375.5	Q9Y6K1-1
DNMT3A	ENST00000264709.7	TSL:1	c.2597+30G>A	intron	N/A	ENSP00000264709.3	Q9Y6K1-1
DNMT3A	ENST00000380746.8	TSL:1	c.2030+30G>A	intron	N/A	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes

AF:

0.455

AC:

69097

AN:

151942

Hom.:

18029

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.582

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.482

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.456

Gnomad FIN

AF:

0.603

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.583

Gnomad OTH

AF:

0.480

GnomAD2 exomes

AF:

0.514

AC:

127888

AN:

248918

AF XY:

0.519

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.539

Gnomad ASJ exome

AF:

0.484

Gnomad EAS exome

AF:

0.285

Gnomad FIN exome

AF:

0.601

Gnomad NFE exome

AF:

0.586

Gnomad OTH exome

AF:

0.529

GnomAD4 exome

AF:

0.559

AC:

798739

AN:

1427862

Hom.:

228680

Cov.:

AF XY:

0.558

AC XY:

397266

AN XY:

711626

show subpopulations

African (AFR)

AF:

0.174

AC:

5676

AN:

32608

American (AMR)

AF:

0.539

AC:

23757

AN:

44106

Ashkenazi Jewish (ASJ)

AF:

0.484

AC:

12518

AN:

25842

East Asian (EAS)

AF:

0.321

AC:

12649

AN:

39394

South Asian (SAS)

AF:

0.479

AC:

40886

AN:

85410

European-Finnish (FIN)

AF:

0.603

AC:

32123

AN:

53314

Middle Eastern (MID)

AF:

0.538

AC:

3050

AN:

5672

European-Non Finnish (NFE)

AF:

0.588

AC:

636926

AN:

1082308

Other (OTH)

AF:

0.526

AC:

31154

AN:

59208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

16391

32781

49172

65562

81953

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17052

34104

51156

68208

85260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.455

AC:

69116

AN:

152060

Hom.:

18032

Cov.:

AF XY:

0.453

AC XY:

33708

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.191

AC:

7927

AN:

41468

American (AMR)

AF:

0.531

AC:

8113

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.482

AC:

1672

AN:

3466

East Asian (EAS)

AF:

0.291

AC:

1506

AN:

5170

South Asian (SAS)

AF:

0.456

AC:

2198

AN:

4818

European-Finnish (FIN)

AF:

0.603

AC:

6378

AN:

10578

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.583

AC:

39629

AN:

67974

Other (OTH)

AF:

0.479

AC:

1010

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1707

3414

5122

6829

8536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

616

1232

1848

2464

3080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.544

Hom.:

98754

Bravo

AF:

0.439

Asia WGS

AF:

0.354

AC:

1235

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.52

(source)

DANN

Benign

0.55

PhyloP100

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over