dbSNP rs2276248: DNMT3L:c.344+62A>G (chr21-44259375-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_175867.3(DNMT3L):c.344+62A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,519,294 control chromosomes in the GnomAD database, including 3,056 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.063 ( 623 hom., cov: 32)

Exomes 𝑓: 0.035 ( 2433 hom. )

Consequence

DNMT3L
NM_175867.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.75

Publications

5 publications found

Variant links:

Genes affected

DNMT3L (HGNC:2980): (DNA methyltransferase 3 like) 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 nuclear protein with similarity to DNA methyltransferases, but is not thought to function as a DNA methyltransferase as it does not contain the amino acid residues necessary for methyltransferase activity. However, it does stimulate de novo methylation by DNA cytosine methyltransferase 3 alpha and is thought to be required for the establishment of maternal genomic imprints. This protein also mediates transcriptional repression through interaction with histone deacetylase 1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2012]

DNMT3L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3L	NM_175867.3 link	c.344+62A>G		intron_variant	Intron 5 of 11	ENST00000628202.3	NP_787063.1	Q9UJW3-1
DNMT3L	NM_013369.4 link	c.344+62A>G		intron_variant	Intron 5 of 11		NP_037501.2	Q9UJW3-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNMT3L	ENST00000628202.3 link	c.344+62A>G	intron_variant	Intron 5 of 11	1	NM_175867.3	ENSP00000486001.1	Q9UJW3-1
DNMT3L	ENST00000270172.7 link	c.344+62A>G	intron_variant	Intron 5 of 11	1		ENSP00000270172.3	Q9UJW3-2
DNMT3L	ENST00000431166.1 link	c.299+62A>G	intron_variant	Intron 4 of 8	5		ENSP00000400242.1	C9J0T5

Frequencies

GnomAD3 genomes

AF:

0.0630

AC:

9573

AN:

152032

Hom.:

619

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0498

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.285

Gnomad SAS

AF:

0.0540

Gnomad FIN

AF:

0.0365

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0589

GnomAD4 exome

AF:

0.0346

AC:

47315

AN:

1367144

Hom.:

2433

AF XY:

0.0343

AC XY:

23438

AN XY:

683274

show subpopulations

African (AFR)

AF:

0.132

AC:

4148

AN:

31462

American (AMR)

AF:

0.0708

AC:

3074

AN:

43420

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

568

AN:

25340

East Asian (EAS)

AF:

0.278

AC:

10843

AN:

38962

South Asian (SAS)

AF:

0.0475

AC:

3971

AN:

83618

European-Finnish (FIN)

AF:

0.0351

AC:

1824

AN:

51968

Middle Eastern (MID)

AF:

0.0375

AC:

183

AN:

4884

European-Non Finnish (NFE)

AF:

0.0197

AC:

20267

AN:

1030444

Other (OTH)

AF:

0.0427

AC:

2437

AN:

57046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

2149

4298

6448

8597

10746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1008

2016

3024

4032

5040

<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:

0.0632

AC:

9618

AN:

152150

Hom.:

623

Cov.:

AF XY:

0.0644

AC XY:

4792

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.124

AC:

5148

AN:

41508

American (AMR)

AF:

0.0499

AC:

764

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3468

East Asian (EAS)

AF:

0.286

AC:

1481

AN:

5182

South Asian (SAS)

AF:

0.0540

AC:

260

AN:

4814

European-Finnish (FIN)

AF:

0.0365

AC:

386

AN:

10584

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0197

AC:

1338

AN:

67982

Other (OTH)

AF:

0.0626

AC:

132

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

434

868

1302

1736

2170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0406

Hom.:

174

Bravo

AF:

0.0688

Asia WGS

AF:

0.157

AC:

544

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.076

(source)

DANN

Benign

0.72

PhyloP100

-1.8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over