14-100729052-A-G

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>G(p.Glu83Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,612 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.071525514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLK1	NM_003836.7	c.248A>G	p.Glu83Gly	missense_variant	3/5	ENST00000341267.9
DLK1	NM_001317172.2	c.248A>G	p.Glu83Gly	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLK1	ENST00000341267.9	c.248A>G	p.Glu83Gly	missense_variant	3/5	1	NM_003836.7	P1
DLK1	ENST00000331224.10	c.248A>G	p.Glu83Gly	missense_variant	3/6	1
DLK1	ENST00000556051.1	c.248A>G	p.Glu83Gly	missense_variant	3/3	2
DLK1	ENST00000392848.9	c.248A>G	p.Glu83Gly	missense_variant	5/6	4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251146 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

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: 0.0000299

Gnomad4 AMR exome AF: 0.00

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 AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74240

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000226 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2023

The c.248A>G (p.E83G) alteration is located in exon 3 (coding exon 3) of the DLK1 gene. This alteration results from a A to G substitution at nucleotide position 248, causing the glutamic acid (E) at amino acid position 83 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	19
Dann	Benign	0.79
DEOGEN2	Benign	0.16	T;T;T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.94	D;.;T;D;D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.072	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N;N;.;N;N
REVEL	Benign	0.24
Sift	Benign	0.47	T;T;.;T;T
Sift4G	Benign	0.34	T;T;.;T;T
Polyphen		0.0, 0.038	.;B;B;B;.
Vest4		0.21, 0.27, 0.14
MutPred		0.47		Gain of catalytic residue at D78 (P = 0);Gain of catalytic residue at D78 (P = 0);Gain of catalytic residue at D78 (P = 0);Gain of catalytic residue at D78 (P = 0);Gain of catalytic residue at D78 (P = 0);
MVP		0.78
MPC		0.44
ClinPred		0.097	T
GERP RS		3.3
Varity_R		0.061
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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;