14-100729021-C-A

Variant names:

• chr14-100729021-C-A
• NM_003836.7:c.217C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003836.7(DLK1):​c.217C>A​(p.Gln73Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q73L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7	c.217C>A	p.Gln73Lys	missense_variant	Exon 3 of 5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2	c.217C>A	p.Gln73Lys	missense_variant	Exon 3 of 6		NP_001304101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9	c.217C>A	p.Gln73Lys	missense_variant	Exon 3 of 5	1	NM_003836.7	ENSP00000340292.4
DLK1	ENST00000331224.10	c.217C>A	p.Gln73Lys	missense_variant	Exon 3 of 6	1		ENSP00000331081.6
DLK1	ENST00000556051.1	c.217C>A	p.Gln73Lys	missense_variant	Exon 3 of 3	2		ENSP00000450821.1
DLK1	ENST00000392848.9	c.217C>A	p.Gln73Lys	missense_variant	Exon 5 of 6	4		ENSP00000376589.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217C>A (p.Q73K) alteration is located in exon 3 (coding exon 3) of the DLK1 gene. This alteration results from a C to A substitution at nucleotide position 217, causing the glutamine (Q) at amino acid position 73 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;D;D;.;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T;.;T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.50	D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	2.0	.;M;M;M;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.7	D;D;.;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0050	D;D;.;D;T
Sift4G	Benign	0.43	T;T;.;T;T
Polyphen		0.68, 0.95	.;P;P;P;.
Vest4		0.63, 0.60, 0.32
MutPred		0.48		Gain of catalytic residue at Q73 (P = 2e-04);Gain of catalytic residue at Q73 (P = 2e-04);Gain of catalytic residue at Q73 (P = 2e-04);Gain of catalytic residue at Q73 (P = 2e-04);Gain of catalytic residue at Q73 (P = 2e-04);
MVP		0.96
MPC		0.58
ClinPred		0.97	D
GERP RS		3.5
Varity_R		0.50
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-101195358;