chr14-100728427-A-G

Variant names:

• chr14-100728427-A-G
• rs13329039
• NM_003836.7:c.99A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_003836.7(DLK1):​c.99A>G​(p.Gln33Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,614,000 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: DLK1 NM_003836.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.429
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-100728427-A-G is Benign according to our data. Variant chr14-100728427-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 731627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.429 with no splicing effect.

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.99A>G	p.Gln33Gln	synonymous	Exon 2 of 5	NP_003827.4
	DLK1	NM_001317172.2		c.99A>G	p.Gln33Gln	synonymous	Exon 2 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.99A>G	p.Gln33Gln	synonymous	Exon 2 of 5	ENSP00000340292.4	P80370-1
	DLK1	ENST00000331224.10	TSL:1	c.99A>G	p.Gln33Gln	synonymous	Exon 2 of 6	ENSP00000331081.6	P80370-2
	DLK1	ENST00000942991.1		c.99A>G	p.Gln33Gln	synonymous	Exon 3 of 6	ENSP00000613050.1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152098 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00611

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000676 AC: 170 AN: 251478 AF XY: 0.000427

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000366 AC: 535 AN: 1461784 Hom.: 1 Cov.: 31 AF XY: 0.000314 AC XY: 228 AN XY: 727194

African (AFR) AF: 0.00645 AC: 216 AN: 33480

American (AMR) AF: 0.00197 AC: 88 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.000147 AC: 163 AN: 1111942

Other (OTH) AF: 0.00106 AC: 64 AN: 60390

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152216 Hom.: 1 Cov.: 30 AF XY: 0.00195 AC XY: 145 AN XY: 74428

African (AFR) AF: 0.00612 AC: 254 AN: 41514

American (AMR) AF: 0.00307 AC: 47 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00113 Hom.: 0

Bravo AF: 0.00263

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.9
DANN	Benign	0.31
PhyloP100		0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs13329039; hg19: chr14-101194764;