Genetic Variant DLK1:p.Asp78Asn (chr14-100729036-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003836.7(DLK1):c.232G>A(p.Asp78Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DLK1
NM_003836.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2951917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7 link	c.232G>A	p.Asp78Asn	missense_variant	Exon 3 of 5	ENST00000341267.9	NP_003827.4	P80370-1A0A024R6L1A8K019
DLK1	NM_001317172.2 link	c.232G>A	p.Asp78Asn	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.232G>A	p.Asp78Asn	missense_variant	Exon 3 of 5	1	NM_003836.7	ENSP00000340292.4	P80370-1
DLK1	ENST00000331224.10 link	c.232G>A	p.Asp78Asn	missense_variant	Exon 3 of 6	1		ENSP00000331081.6	P80370-2
DLK1	ENST00000556051.1 link	c.232G>A	p.Asp78Asn	missense_variant	Exon 3 of 3	2		ENSP00000450821.1	G3V2R7
DLK1	ENST00000392848.9 link	c.232G>A	p.Asp78Asn	missense_variant	Exon 5 of 6	4		ENSP00000376589.5	G3XAH5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251264

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232G>A (p.D78N) alteration is located in exon 3 (coding exon 3) of the DLK1 gene. This alteration results from a G to A substitution at nucleotide position 232, causing the aspartic acid (D) at amino acid position 78 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.86

D;.;T;T;D

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.30

T;T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.80

.;N;N;N;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.7

N;N;.;N;N

REVEL

Benign

0.25

Sift

Benign

0.12

T;T;.;T;D

Sift4G

Uncertain

0.025

D;T;.;T;D

Polyphen

0.023, 0.086

.;B;B;B;.

Vest4

0.29, 0.31, 0.21

MVP

0.97

MPC

0.37

ClinPred

0.36

GERP RS

4.4

Varity_R

0.10

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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