chr14-100729029-T-G

Position:

• chr14-100729029-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003836.7(DLK1):​c.225T>G​(p.Ile75Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.166

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2747919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLK1	NM_003836.7	c.225T>G	p.Ile75Met	missense_variant	3/5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2	c.225T>G	p.Ile75Met	missense_variant	3/6		NP_001304101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9	c.225T>G	p.Ile75Met	missense_variant	3/5	1	NM_003836.7	ENSP00000340292	P1
DLK1	ENST00000331224.10	c.225T>G	p.Ile75Met	missense_variant	3/6	1		ENSP00000331081
DLK1	ENST00000556051.1	c.225T>G	p.Ile75Met	missense_variant	3/3	2		ENSP00000450821
DLK1	ENST00000392848.9	c.225T>G	p.Ile75Met	missense_variant	5/6	4		ENSP00000376589

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2023

The c.225T>G (p.I75M) alteration is located in exon 3 (coding exon 3) of the DLK1 gene. This alteration results from a T to G substitution at nucleotide position 225, causing the isoleucine (I) at amino acid position 75 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	1.8
DANN	Uncertain	0.97
DEOGEN2	Benign	0.14	T;T;T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.84	T;.;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.5	.;M;M;M;.
MutationTaster	Benign	0.88	D;D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.95	N;N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.033	D;T;.;T;D
Sift4G	Benign	0.088	T;T;.;T;T
Polyphen		0.37, 0.63	.;B;B;P;.
Vest4		0.36, 0.35, 0.23
MutPred		0.40		Gain of catalytic residue at Q73 (P = 0);Gain of catalytic residue at Q73 (P = 0);Gain of catalytic residue at Q73 (P = 0);Gain of catalytic residue at Q73 (P = 0);Gain of catalytic residue at Q73 (P = 0);
MVP		0.96
MPC		0.38
ClinPred		0.16	T
GERP RS		-0.97
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.10
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr14-101195366;