chr14-100732060-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_003836.7(DLK1):c.281C>T(p.Ser94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
DLK1
NM_003836.7 missense
NM_003836.7 missense
Scores
2
9
7
Clinical Significance
Conservation
PhyloP100: 2.84
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a glycosylation_site O-linked (GalNAc...) serine (size 0) in uniprot entity DLK1_HUMAN
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DLK1 | NM_003836.7 | c.281C>T | p.Ser94Leu | missense_variant | 4/5 | ENST00000341267.9 | |
DLK1 | NM_001317172.2 | c.281C>T | p.Ser94Leu | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DLK1 | ENST00000341267.9 | c.281C>T | p.Ser94Leu | missense_variant | 4/5 | 1 | NM_003836.7 | P1 | |
DLK1 | ENST00000331224.10 | c.281C>T | p.Ser94Leu | missense_variant | 4/6 | 1 | |||
DLK1 | ENST00000392848.9 | c.281C>T | p.Ser94Leu | missense_variant | 6/6 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152240Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250670Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135500
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461322Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10AN XY: 726958
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152358Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4AN XY: 74494
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2023 | The c.281C>T (p.S94L) alteration is located in exon 4 (coding exon 4) of the DLK1 gene. This alteration results from a C to T substitution at nucleotide position 281, causing the serine (S) at amino acid position 94 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;.;D
REVEL
Uncertain
Sift
Uncertain
D;D;.;D
Sift4G
Uncertain
D;D;.;T
Polyphen
1.0
.;D;D;D
Vest4
0.24, 0.24
MVP
MPC
1.1
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at