14-100734308-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_003836.7(DLK1):c.564T>C(p.Ile188=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 1,613,058 control chromosomes in the GnomAD database, including 252,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.62 (30798 hom., cov: 33)
  • Exomes 𝑓: 0.54 (221227 hom.)
• Consequence: DLK1 NM_003836.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.449

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 14-100734308-T-C is Benign according to our data. Variant chr14-100734308-T-C is described in ClinVar as [Benign]. Clinvar id is 3059696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.449 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLK1	NM_003836.7	c.564T>C	p.Ile188=	synonymous_variant	5/5	ENST00000341267.9
DLK1	NM_001317172.2	c.564T>C	p.Ile188=	synonymous_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLK1	ENST00000341267.9	c.564T>C	p.Ile188=	synonymous_variant	5/5	1	NM_003836.7	P1
DLK1	ENST00000331224.10	c.564T>C	p.Ile188=	synonymous_variant	5/6	1

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94432 AN: 151990 Hom.: 30742 Cov.: 33

Gnomad AFR AF: 0.738

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.596

GnomAD3 exomes AF: 0.629 AC: 157523 AN: 250360 Hom.: 52434 AF XY: 0.616 AC XY: 83541 AN XY: 135612

Gnomad AFR exome AF: 0.745

Gnomad AMR exome AF: 0.766

Gnomad ASJ exome AF: 0.550

Gnomad EAS exome AF: 0.998

Gnomad SAS exome AF: 0.644

Gnomad FIN exome AF: 0.681

Gnomad NFE exome AF: 0.507

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.539 AC: 787008 AN: 1460952 Hom.: 221227 Cov.: 94 AF XY: 0.539 AC XY: 392117 AN XY: 726816

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.751

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.672

Gnomad4 NFE exome AF: 0.492

Gnomad4 OTH exome AF: 0.568

GnomAD4 genome AF: 0.622 AC: 94548 AN: 152106 Hom.: 30798 Cov.: 33 AF XY: 0.633 AC XY: 47033 AN XY: 74346

Gnomad4 AFR AF: 0.739

Gnomad4 AMR AF: 0.659

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.996

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.687

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.601

Alfa AF: 0.528 Hom.: 42346

Bravo AF: 0.624

Asia WGS AF: 0.854 AC: 2967 AN: 3478

EpiCase AF: 0.490

EpiControl AF: 0.489

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DLK1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	3.0
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs1802710; hg19: chr14-101200645; COSMIC: COSV57990562; COSMIC: COSV57990562;