14-100728431-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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
NM_003836.7 missense
Scores
12
5
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DLK1 | NM_003836.7 | c.103G>C | p.Gly35Arg | missense_variant | 2/5 | ENST00000341267.9 | |
DLK1 | NM_001317172.2 | c.103G>C | p.Gly35Arg | missense_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DLK1 | ENST00000341267.9 | c.103G>C | p.Gly35Arg | missense_variant | 2/5 | 1 | NM_003836.7 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Silver-Russell syndrome 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Departement de Genetique, Biologie Moleculaire Endocrinienne, Assistance Publique–Hôpitaux de Paris, Hopital Trousseau | Apr 15, 2021 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
T;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;D;D
Sift4G
Uncertain
D;D;.;D;D
Polyphen
1.0
.;D;D;D;.
Vest4
0.97, 0.92, 0.98
MutPred
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
MPC
1.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.