14-100732089-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003836.7(DLK1):c.310G>A(p.Val104Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,613,922 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0049 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (144 hom.)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0370

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031697452).
• BP6: Variant 14-100732089-G-A is Benign according to our data. Variant chr14-100732089-G-A is described in ClinVar as [Benign]. Clinvar id is 782883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLK1	NM_003836.7	c.310G>A	p.Val104Met	missense_variant	4/5	ENST00000341267.9
DLK1	NM_001317172.2	c.310G>A	p.Val104Met	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLK1	ENST00000341267.9	c.310G>A	p.Val104Met	missense_variant	4/5	1	NM_003836.7	P1
DLK1	ENST00000331224.10	c.310G>A	p.Val104Met	missense_variant	4/6	1
DLK1	ENST00000392848.9			downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152228 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0618

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00907 AC: 2277 AN: 251160 Hom.: 55 AF XY: 0.00843 AC XY: 1145 AN XY: 135760

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0665

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.000986

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00356 AC: 5202 AN: 1461576 Hom.: 144 Cov.: 33 AF XY: 0.00353 AC XY: 2566 AN XY: 727098

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0100

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0733

Gnomad4 SAS exome AF: 0.00310

Gnomad4 FIN exome AF: 0.0175

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.00507

GnomAD4 genome AF: 0.00492 AC: 749 AN: 152346 Hom.: 11 Cov.: 33 AF XY: 0.00616 AC XY: 459 AN XY: 74492

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0612

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0227

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00286 Hom.: 31

Bravo AF: 0.00480

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00875 AC: 1062

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DLK1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	5.4
Dann	Benign	0.93
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.78	N;.;N
REVEL	Benign	0.25
Sift	Benign	0.15	T;.;T
Sift4G	Benign	0.10	T;.;T
Polyphen		0.37	B;B;B
Vest4		0.079
MVP		0.87
MPC		0.43
ClinPred		0.0055	T
GERP RS		-0.11
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.095
gMVP		0.48

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: rs2273607; hg19: chr14-101198426; COSMIC: COSV57991531; COSMIC: COSV57991531;