14-100728998-A-C

Variant names:

• chr14-100728998-A-C
• NM_003836.7:c.194A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003836.7(DLK1):​c.194A>C​(p.His65Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 7.52

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7	c.194A>C	p.His65Pro	missense_variant	Exon 3 of 5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2	c.194A>C	p.His65Pro	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.194A>C	p.His65Pro	missense_variant	Exon 3 of 5	1	NM_003836.7	ENSP00000340292.4
DLK1	ENST00000331224.10	c.194A>C	p.His65Pro	missense_variant	Exon 3 of 6	1		ENSP00000331081.6
DLK1	ENST00000556051.1	c.194A>C	p.His65Pro	missense_variant	Exon 3 of 3	2		ENSP00000450821.1
DLK1	ENST00000392848.9	c.194A>C	p.His65Pro	missense_variant	Exon 5 of 6	4		ENSP00000376589.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

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	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.76
DEOGEN2	Benign	0.36	T;D;D;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.083
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;.;T;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	.;M;M;M;.
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-9.0	D;D;.;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D;D;.;D;D
Sift4G	Uncertain	0.012	D;D;.;T;D
Polyphen		0.36, 0.90	.;B;B;P;.
Vest4		0.58, 0.56, 0.48
MutPred		0.46		Gain of catalytic residue at L64 (P = 0);Gain of catalytic residue at L64 (P = 0);Gain of catalytic residue at L64 (P = 0);Gain of catalytic residue at L64 (P = 0);Gain of catalytic residue at L64 (P = 0);
MVP		0.96
MPC		0.91
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.54
gMVP		0.94

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: chr14-101195335;