rs2273607

Variant names:

• chr14-100732089-G-A
• rs2273607
• NM_003836.7:c.310G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-100732089-G-A
• chr14-100732089-G-C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: -0.0370
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003836.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLK1	NM_003836.7	MANE Select	c.310G>A	p.Val104Met	missense	Exon 4 of 5	NP_003827.4
	DLK1	NM_001317172.2		c.310G>A	p.Val104Met	missense	Exon 4 of 6	NP_001304101.2	P80370-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLK1	ENST00000341267.9	TSL:1 MANE Select	c.310G>A	p.Val104Met	missense	Exon 4 of 5	ENSP00000340292.4	P80370-1
	DLK1	ENST00000331224.10	TSL:1	c.310G>A	p.Val104Met	missense	Exon 4 of 6	ENSP00000331081.6	P80370-2
	DLK1	ENST00000942991.1		c.310G>A	p.Val104Met	missense	Exon 5 of 6	ENSP00000613050.1

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

GnomAD2 exomes AF: 0.00907 AC: 2277 AN: 251160 AF XY: 0.00843

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33470

American (AMR) AF: 0.0100 AC: 447 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26130

East Asian (EAS) AF: 0.0733 AC: 2910 AN: 39676

South Asian (SAS) AF: 0.00310 AC: 267 AN: 86224

European-Finnish (FIN) AF: 0.0175 AC: 936 AN: 53404

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000290 AC: 322 AN: 1111818

Other (OTH) AF: 0.00507 AC: 306 AN: 60378

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

African (AFR) AF: 0.000313 AC: 13 AN: 41588

American (AMR) AF: 0.00817 AC: 125 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0612 AC: 317 AN: 5180

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.0227 AC: 241 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68036

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00263 Hom.: 34

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	DLK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.037
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.25
Sift	Benign	0.15	T
Sift4G	Benign	0.10	T
Polyphen		0.37	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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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