Genetic Variant DNMT3L:p.Ser339Leu (chr21-44246542-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_175867.3(DNMT3L):c.1016C>T(p.Ser339Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S339W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 0)

Consequence

DNMT3L
NM_175867.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.082122594).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175867.3. 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
	DNMT3L	NM_175867.3	MANE Select	c.1016C>T	p.Ser339Leu	missense	Exon 12 of 12	NP_787063.1	Q9UJW3-1
	DNMT3L	NM_013369.4		c.1019C>T	p.Ser340Leu	missense	Exon 12 of 12	NP_037501.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT3L	ENST00000628202.3	TSL:1 MANE Select	c.1016C>T	p.Ser339Leu	missense	Exon 12 of 12	ENSP00000486001.1	Q9UJW3-1
DNMT3L	ENST00000270172.7	TSL:1	c.1019C>T	p.Ser340Leu	missense	Exon 12 of 12	ENSP00000270172.3	Q9UJW3-2
DNMT3L	ENST00000436357.5	TSL:3	n.400C>T		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

246940

AF XY:

0.0000149

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.076

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.52

M_CAP

Benign

0.0050

MetaRNN

Benign

0.082

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

1.7

PrimateAI

Benign

0.27

PROVEAN

Benign

0.97

REVEL

Benign

0.11

Sift

Benign

0.27

Sift4G

Benign

0.43

Polyphen

0.028

Vest4

0.14

MVP

0.29

MPC

0.13

ClinPred

0.069

GERP RS

3.3

Varity_R

0.21

gMVP

0.30

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over