rs147224004

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_003836.7(DLK1):c.194A>G(p.His65Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000902 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00094 ( 0 hom. )

Consequence

DLK1
NM_003836.7 missense

Scores

Clinical Significance

Benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 7.52

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14345995).

BP6

Variant 14-100728998-A-G is Benign according to our data. Variant chr14-100728998-A-G is described in ClinVar as [Benign]. Clinvar id is 1064522.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7 link	c.194A>G	p.His65Arg	missense_variant	Exon 3 of 5	ENST00000341267.9	NP_003827.4	P80370-1A0A024R6L1A8K019
DLK1	NM_001317172.2 link	c.194A>G	p.His65Arg	missense_variant	Exon 3 of 6		NP_001304101.2	P80370-2A8K019

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLK1	ENST00000341267.9 link	c.194A>G	p.His65Arg	missense_variant	Exon 3 of 5	1	NM_003836.7	ENSP00000340292.4	P80370-1
DLK1	ENST00000331224.10 link	c.194A>G	p.His65Arg	missense_variant	Exon 3 of 6	1		ENSP00000331081.6	P80370-2
DLK1	ENST00000556051.1 link	c.194A>G	p.His65Arg	missense_variant	Exon 3 of 3	2		ENSP00000450821.1	G3V2R7
DLK1	ENST00000392848.9 link	c.194A>G	p.His65Arg	missense_variant	Exon 5 of 6	4		ENSP00000376589.5	G3XAH5

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000477

AC:

120

AN:

251434

Hom.:

AF XY:

0.000478

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000985

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000943

AC:

1378

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000924

AC XY:

672

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.00120

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000513

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000417

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000514

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.00136

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Silver-Russell syndrome 1

Uncertain:1

Apr 15, 2021

Departement de Genetique, Biologie Moleculaire Endocrinienne, Assistance Publique–Hôpitaux de Paris, Hopital Trousseau

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.(His65Arg) has been identified in the heterozygous state in a patient with a clinical suspicion of Silver Russell syndrome. ). His65 is located within the second EGF-like motif of the extracellular domain of DLK1. This variant was inherited from her healthy mother, who carried the same heterozygous variant. As DLK1 is a maternally imprinted/paternally expressed gene, this variant is unlikely to explain the phenotype of the patient -

not provided

Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DLK1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.35

T;D;D;.;.

Eigen

Benign

-0.040

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;.;T;D;D

M_CAP

Uncertain

0.085

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.2

.;M;M;M;.

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-7.0

D;D;.;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0040

D;D;.;D;D

Sift4G

Uncertain

0.013

D;T;.;T;D

Polyphen

0.21, 0.55

.;B;B;P;.

Vest4

0.39, 0.42, 0.33

MVP

0.99

MPC

0.52

ClinPred

0.16

GERP RS

4.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.44

gMVP

0.85

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