14-100729070-G-A

Position:

• chr14-100729070-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_003836.7(DLK1):​c.262+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLK1 NM_003836.7 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0004320
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.488

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.218042).
• BP6: Variant 14-100729070-G-A is Benign according to our data. Variant chr14-100729070-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3030180.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLK1	NM_003836.7	c.262+4G>A		splice_donor_region_variant, intron_variant		ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2	c.262+4G>A		splice_donor_region_variant, intron_variant			NP_001304101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9	c.262+4G>A		splice_donor_region_variant, intron_variant		1	NM_003836.7	ENSP00000340292	P1
DLK1	ENST00000331224.10	c.262+4G>A		splice_donor_region_variant, intron_variant		1		ENSP00000331081
DLK1	ENST00000556051.1	c.266G>A	p.Trp89Ter	stop_gained	3/3	2		ENSP00000450821
DLK1	ENST00000392848.9	c.262+4G>A		splice_donor_region_variant, intron_variant		4		ENSP00000376589

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DLK1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2023

This variant is classified as likely 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_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Uncertain	0.99
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.75	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.16
GERP RS		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.084
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: rs2036476347; hg19: chr14-101195407;