14-100729010-G-C

Variant names:

• chr14-100729010-G-C
• NM_003836.7:c.206G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003836.7(DLK1):​c.206G>C​(p.Gly69Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 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: 6.8e-7 (0 hom.)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.708

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036145687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7	c.206G>C	p.Gly69Ala	missense_variant	Exon 3 of 5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2	c.206G>C	p.Gly69Ala	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.206G>C	p.Gly69Ala	missense_variant	Exon 3 of 5	1	NM_003836.7	ENSP00000340292.4
DLK1	ENST00000331224.10	c.206G>C	p.Gly69Ala	missense_variant	Exon 3 of 6	1		ENSP00000331081.6
DLK1	ENST00000556051.1	c.206G>C	p.Gly69Ala	missense_variant	Exon 3 of 3	2		ENSP00000450821.1
DLK1	ENST00000392848.9	c.206G>C	p.Gly69Ala	missense_variant	Exon 5 of 6	4		ENSP00000376589.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.2
DANN	Benign	0.31
DEOGEN2	Benign	0.083	T;T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.78	T;.;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.036	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.34	.;N;N;N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.65	N;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.71	T;T;.;T;T
Sift4G	Benign	0.74	T;T;.;T;T
Polyphen		0.0, 0.011	.;B;B;B;.
Vest4		0.21, 0.24, 0.084
MutPred		0.47		Gain of catalytic residue at H65 (P = 0);Gain of catalytic residue at H65 (P = 0);Gain of catalytic residue at H65 (P = 0);Gain of catalytic residue at H65 (P = 0);Gain of catalytic residue at H65 (P = 0);
MVP		0.78
MPC		0.40
ClinPred		0.040	T
GERP RS		-1.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.034
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr14-101195347;