Genetic Variant DNMT3L:c.-8+44G>A (chr21-44261696-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_175867.3(DNMT3L):c.-8+44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 167,914 control chromosomes in the GnomAD database, including 1,139 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 0.11 ( 1084 hom., cov: 31)

Exomes 𝑓: 0.073 ( 55 hom. )

Consequence

DNMT3L
NM_175867.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.72

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3L	NM_175867.3 link	c.-8+44G>A		intron_variant	Intron 1 of 11	ENST00000628202.3	NP_787063.1	Q9UJW3-1
DNMT3L	NM_013369.4 link	c.-8+44G>A		intron_variant	Intron 1 of 11		NP_037501.2	Q9UJW3-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNMT3L	ENST00000628202.3 link	c.-8+44G>A	intron_variant	Intron 1 of 11	1	NM_175867.3	ENSP00000486001.1	Q9UJW3-1
DNMT3L	ENST00000270172.7 link	c.-8+44G>A	intron_variant	Intron 1 of 11	1		ENSP00000270172.3	Q9UJW3-2
DNMT3L	ENST00000431166.1 link	c.-8+44G>A	intron_variant	Intron 1 of 8	5		ENSP00000400242.1	C9J0T5

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16279

AN:

152078

Hom.:

1084

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.132

Gnomad AMR

AF:

0.0744

Gnomad ASJ

AF:

0.0953

Gnomad EAS

AF:

0.00464

Gnomad SAS

AF:

0.137

Gnomad FIN

AF:

0.0837

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.0880

Gnomad OTH

AF:

0.0941

GnomAD4 exome

AF:

0.0728

AC:

1145

AN:

15718

Hom.:

Cov.:

AF XY:

0.0782

AC XY:

645

AN XY:

8244

show subpopulations

African (AFR)

AF:

0.140

AC:

AN:

292

American (AMR)

AF:

0.0492

AC:

AN:

1788

Ashkenazi Jewish (ASJ)

AF:

0.0745

AC:

AN:

322

East Asian (EAS)

AF:

0.0290

AC:

AN:

620

South Asian (SAS)

AF:

0.111

AC:

173

AN:

1558

European-Finnish (FIN)

AF:

0.0588

AC:

AN:

510

Middle Eastern (MID)

AF:

0.0652

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0725

AC:

707

AN:

9754

Other (OTH)

AF:

0.0737

AC:

AN:

828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.107

AC:

16290

AN:

152196

Hom.:

1084

Cov.:

AF XY:

0.106

AC XY:

7890

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.166

AC:

6897

AN:

41514

American (AMR)

AF:

0.0743

AC:

1136

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0953

AC:

331

AN:

3472

East Asian (EAS)

AF:

0.00465

AC:

AN:

5160

South Asian (SAS)

AF:

0.137

AC:

663

AN:

4826

European-Finnish (FIN)

AF:

0.0837

AC:

889

AN:

10616

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0881

AC:

5988

AN:

67990

Other (OTH)

AF:

0.0931

AC:

197

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

728

1455

2183

2910

3638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<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:

0.0911

Hom.:

870

Bravo

AF:

0.108

Asia WGS

AF:

0.0810

AC:

284

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

9.4

(source)

DANN

Benign

0.66

PhyloP100

-2.7

PromoterAI

0.057

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.31

Position offset: 3

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