14-100729052-A-T

Variant names:

• chr14-100729052-A-T
• rs761906566
• NM_003836.7:c.248A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003836.7(DLK1):​c.248A>T​(p.Glu83Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08190736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7	c.248A>T	p.Glu83Val	missense_variant	Exon 3 of 5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2	c.248A>T	p.Glu83Val	missense_variant	Exon 3 of 6		NP_001304101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9	c.248A>T	p.Glu83Val	missense_variant	Exon 3 of 5	1	NM_003836.7	ENSP00000340292.4
DLK1	ENST00000331224.10	c.248A>T	p.Glu83Val	missense_variant	Exon 3 of 6	1		ENSP00000331081.6
DLK1	ENST00000556051.1	c.248A>T	p.Glu83Val	missense_variant	Exon 3 of 3	2		ENSP00000450821.1
DLK1	ENST00000392848.9	c.248A>T	p.Glu83Val	missense_variant	Exon 5 of 6	4		ENSP00000376589.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251146 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461612 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000226 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.65
DEOGEN2	Benign	0.13	T;T;T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.91	D;.;T;D;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.20	.;N;N;N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.74	N;N;.;N;N
REVEL	Benign	0.26
Sift	Benign	0.24	T;D;.;T;T
Sift4G	Benign	0.26	T;T;.;T;T
Polyphen		0.0020, 0.18	.;B;B;B;.
Vest4		0.24, 0.27, 0.14
MutPred		0.47		Gain of catalytic residue at E83 (P = 0);Gain of catalytic residue at E83 (P = 0);Gain of catalytic residue at E83 (P = 0);Gain of catalytic residue at E83 (P = 0);Gain of catalytic residue at E83 (P = 0);
MVP		0.71
MPC		0.44
ClinPred		0.15	T
GERP RS		3.3
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.10
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs761906566; hg19: chr14-101195389;