14-100729185-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003836.7(DLK1):c.262+119C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,488,892 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (57 hom.)
• Consequence: DLK1 NM_003836.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.413

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-100729185-C-T is Benign according to our data. Variant chr14-100729185-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2644535.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLK1	NM_003836.7	c.262+119C>T		intron_variant		ENST00000341267.9
DLK1	NM_001317172.2	c.262+119C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLK1	ENST00000341267.9	c.262+119C>T		intron_variant		1	NM_003836.7	P1
DLK1	ENST00000331224.10	c.262+119C>T		intron_variant		1
DLK1	ENST00000556051.1	c.381C>T	p.Ser127=	synonymous_variant	3/3	2
DLK1	ENST00000392848.9	c.262+119C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00633 AC: 964 AN: 152218 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00679 AC: 1270 AN: 187154 Hom.: 6 AF XY: 0.00623 AC XY: 637 AN XY: 102202

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.0275

Gnomad EAS exome AF: 0.0000680

Gnomad SAS exome AF: 0.00205

Gnomad FIN exome AF: 0.00604

Gnomad NFE exome AF: 0.00952

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00689 AC: 9208 AN: 1336556 Hom.: 57 Cov.: 22 AF XY: 0.00697 AC XY: 4652 AN XY: 667352

Gnomad4 AFR exome AF: 0.000835

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.00577

Gnomad4 NFE exome AF: 0.00742

Gnomad4 OTH exome AF: 0.00652

GnomAD4 genome AF: 0.00633 AC: 964 AN: 152336 Hom.: 8 Cov.: 32 AF XY: 0.00612 AC XY: 456 AN XY: 74486

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.0337

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.0143 Hom.: 6

Bravo AF: 0.00515

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

DLK1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.4
Dann	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs117667438; hg19: chr14-101195522;