14-100728976-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_003836.7(DLK1):c.172G>A(p.Val58Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,948 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.210

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=0.10702491).
• BP6: Variant 14-100728976-G-A is Benign according to our data. Variant chr14-100728976-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2362974.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLK1	NM_003836.7	c.172G>A	p.Val58Met	missense_variant	3/5	ENST00000341267.9
DLK1	NM_001317172.2	c.172G>A	p.Val58Met	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLK1	ENST00000341267.9	c.172G>A	p.Val58Met	missense_variant	3/5	1	NM_003836.7	P1
DLK1	ENST00000331224.10	c.172G>A	p.Val58Met	missense_variant	3/6	1
DLK1	ENST00000556051.1	c.172G>A	p.Val58Met	missense_variant	3/3	2
DLK1	ENST00000392848.9	c.172G>A	p.Val58Met	missense_variant	5/6	4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251392 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135880

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000597

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: 0.0000701

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	0.060
Dann	Benign	0.86
DEOGEN2	Benign	0.31	T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.72	T;.;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N;N;.;N;N
REVEL	Benign	0.18
Sift	Benign	0.056	T;T;.;D;T
Sift4G	Uncertain	0.060	T;T;.;T;D
Polyphen		0.013, 0.078	.;B;B;B;.
Vest4		0.36, 0.40, 0.15
MutPred		0.30		Gain of catalytic residue at L53 (P = 0.001);Gain of catalytic residue at L53 (P = 0.001);Gain of catalytic residue at L53 (P = 0.001);Gain of catalytic residue at L53 (P = 0.001);Gain of catalytic residue at L53 (P = 0.001);
MVP		0.83
MPC		0.37
ClinPred		0.054	T
GERP RS		-0.60
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.034
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs776598670; hg19: chr14-101195313;