14-100732089-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003836.7(DLK1):c.310G>A(p.Val104Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,613,922 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0049 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 144 hom. )

Consequence

DLK1
NM_003836.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0370

Variant links:

Genes affected

DLK1 (HGNC:2907): (delta like non-canonical Notch ligand 1) This gene encodes a transmembrane protein that contains multiple epidermal growth factor repeats that functions as a regulator of cell growth. The encoded protein is involved in the differentiation of several cell types including adipocytes. This gene is located in a region of chromosome 14 frequently showing unparental disomy, and is imprinted and expressed from the paternal allele. A single nucleotide variant in this gene is associated with child and adolescent obesity and shows polar overdominance, where heterozygotes carrying an active paternal allele express the phenotype, while mutant homozygotes are normal. [provided by RefSeq, Nov 2015]

DLK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031697452).

BP6

Variant 14-100732089-G-A is Benign according to our data. Variant chr14-100732089-G-A is described in ClinVar as [Benign]. Clinvar id is 782883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7 link	c.310G>A	p.Val104Met	missense_variant	Exon 4 of 5	ENST00000341267.9	NP_003827.4	P80370-1A0A024R6L1A8K019
DLK1	NM_001317172.2 link	c.310G>A	p.Val104Met	missense_variant	Exon 4 of 6		NP_001304101.2	P80370-2A8K019

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLK1	ENST00000341267.9 link	c.310G>A	p.Val104Met	missense_variant	Exon 4 of 5	1	NM_003836.7	ENSP00000340292.4	P80370-1
DLK1	ENST00000331224.10 link	c.310G>A	p.Val104Met	missense_variant	Exon 4 of 6	1		ENSP00000331081.6	P80370-2
DLK1	ENST00000392848.9 link	c.*19G>A		downstream_gene_variant		4		ENSP00000376589.5	G3XAH5

Frequencies

GnomAD3 genomes

AF:

0.00496

AC:

755

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00824

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0618

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00907

AC:

2277

AN:

251160

Hom.:

AF XY:

0.00843

AC XY:

1145

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0665

Gnomad SAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.000986

Gnomad OTH exome

AF:

0.00604

GnomAD4 exome

AF:

0.00356

AC:

5202

AN:

1461576

Hom.:

144

Cov.:

AF XY:

0.00353

AC XY:

2566

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0100

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0733

Gnomad4 SAS exome

AF:

0.00310

Gnomad4 FIN exome

AF:

0.0175

Gnomad4 NFE exome

AF:

0.000290

Gnomad4 OTH exome

AF:

0.00507

GnomAD4 genome

AF:

0.00492

AC:

749

AN:

152346

Hom.:

Cov.:

AF XY:

0.00616

AC XY:

459

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00817

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0612

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.0227

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00286

Hom.:

Bravo

AF:

0.00480

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00875

AC:

1062

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DLK1-related disorder

Benign:1

Apr 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.41

CADD

Benign

5.4

DANN

Benign

0.93

DEOGEN2

Uncertain

0.54

D;D;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.78

.;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

2.0

M;M;M

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.78

N;.;N

REVEL

Benign

0.25

Sift

Benign

0.15

T;.;T

Sift4G

Benign

0.10

T;.;T

Polyphen

0.37

B;B;B

Vest4

0.079

MVP

0.87

MPC

0.43

ClinPred

0.0055

GERP RS

-0.11

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.095

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over