14-100729022-A-T

Position:

chr14-100729022-A-T

Variant summary

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

The NM_003836.7(DLK1):c.218A>T(p.Gln73Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,052 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.019 ( 81 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 76 hom. )

Consequence

DLK1
NM_003836.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 9.27

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=0.010512531).

BP6

Variant 14-100729022-A-T is Benign according to our data. Variant chr14-100729022-A-T is described in ClinVar as [Benign]. Clinvar id is 779740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLK1	NM_003836.7 linkuse as main transcript	c.218A>T	p.Gln73Leu	missense_variant	3/5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2 linkuse as main transcript	c.218A>T	p.Gln73Leu	missense_variant	3/6		NP_001304101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9 linkuse as main transcript	c.218A>T	p.Gln73Leu	missense_variant	3/5	1	NM_003836.7	ENSP00000340292	P1	P80370-1
DLK1	ENST00000331224.10 linkuse as main transcript	c.218A>T	p.Gln73Leu	missense_variant	3/6	1		ENSP00000331081		P80370-2
DLK1	ENST00000556051.1 linkuse as main transcript	c.218A>T	p.Gln73Leu	missense_variant	3/3	2		ENSP00000450821
DLK1	ENST00000392848.9 linkuse as main transcript	c.218A>T	p.Gln73Leu	missense_variant	5/6	4		ENSP00000376589

Frequencies

GnomAD3 genomes

AF:

0.0187

AC:

2837

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00470

AC:

1182

AN:

251398

Hom.:

AF XY:

0.00338

AC XY:

459

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0661

Gnomad AMR exome

AF:

0.00237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00180

AC:

2632

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1141

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0664

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.00349

GnomAD4 genome

AF:

0.0186

AC:

2838

AN:

152234

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1332

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0648

Gnomad4 AMR

AF:

0.00706

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.0210

ESP6500AA

AF:

0.0713

AC:

314

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00591

AC:

718

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;D;D;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.66

T;.;T;T;T

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Pathogenic

3.2

.;M;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-6.7

D;D;.;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;D;.;D;D

Sift4G

Uncertain

0.027

D;D;.;T;D

Polyphen

0.91, 0.99

.;P;P;D;.

Vest4

0.71, 0.67, 0.65

MVP

0.94

MPC

0.65

ClinPred

0.072

GERP RS

4.4

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.65

gMVP

0.76

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

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