NM_003836.7:c.67+78C>T

Variant names:

• chr14-100727213-C-T
• rs2036445636
• NM_003836.7:c.67+78C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003836.7(DLK1):​c.67+78C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000008 in 1,250,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: DLK1 NM_003836.7 intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.177
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).

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.67+78C>T		intron	N/A	NP_003827.4
	DLK1	NM_001317172.2		c.67+78C>T		intron	N/A	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.67+78C>T		intron	N/A	ENSP00000340292.4	P80370-1
	DLK1	ENST00000331224.10	TSL:1	c.67+78C>T		intron	N/A	ENSP00000331081.6	P80370-2
	DLK1	ENST00000942991.1		c.67+78C>T		intron	N/A	ENSP00000613050.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.00e-7 AC: 1 AN: 1250004 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 613680

African (AFR) AF: 0.00 AC: 0 AN: 25984

American (AMR) AF: 0.00 AC: 0 AN: 27512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20856

East Asian (EAS) AF: 0.00 AC: 0 AN: 30750

South Asian (SAS) AF: 0.0000147 AC: 1 AN: 68126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4354

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 986400

Other (OTH) AF: 0.00 AC: 0 AN: 51616

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Central precocious puberty (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.96
PhyloP100		0.18
PromoterAI		0.015	Neutral
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

Other links and lift over

dbSNP: rs2036445636; hg19: chr14-101193550;