14-100728431-G-C

Variant names:

• chr14-100728431-G-C
• NM_003836.7:c.103G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003836.7(DLK1):​c.103G>C​(p.Gly35Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.95

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7	c.103G>C	p.Gly35Arg	missense_variant	Exon 2 of 5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2	c.103G>C	p.Gly35Arg	missense_variant	Exon 2 of 6		NP_001304101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9	c.103G>C	p.Gly35Arg	missense_variant	Exon 2 of 5	1	NM_003836.7	ENSP00000340292.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

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.(Gly35Arg) has been identified in the heterozygous state in a patient with a clinical suspicion of Silver Russell syndrome. Gly35 is located within the first EGF-like motif in 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T;D;D;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.5	.;M;M;M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.9	D;D;.;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Uncertain	0.0090	D;D;.;D;D
Polyphen		1.0	.;D;D;D;.
Vest4		0.97, 0.92, 0.98
MutPred		0.71		Gain of catalytic residue at G35 (P = 0.0042);Gain of catalytic residue at G35 (P = 0.0042);Gain of catalytic residue at G35 (P = 0.0042);Gain of catalytic residue at G35 (P = 0.0042);Gain of catalytic residue at G35 (P = 0.0042);
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-101194768;