chr14-100729022-A-T

Position:

• chr14-100729022-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003836.7(DLK1):​c.218A>T​(p.Gln73Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,614,052 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.019 (81 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (76 hom.)
• Consequence: DLK1 NM_003836.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.27

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010512531).
• BP6: Variant 14-100729022-A-T is Benign according to our data. Variant chr14-100729022-A-T is described in ClinVar as [Benign]. Clinvar id is 779740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLK1	NM_003836.7	c.218A>T	p.Gln73Leu	missense_variant	3/5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2	c.218A>T	p.Gln73Leu	missense_variant	3/6		NP_001304101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9	c.218A>T	p.Gln73Leu	missense_variant	3/5	1	NM_003836.7	ENSP00000340292	P1
DLK1	ENST00000331224.10	c.218A>T	p.Gln73Leu	missense_variant	3/6	1		ENSP00000331081
DLK1	ENST00000556051.1	c.218A>T	p.Gln73Leu	missense_variant	3/3	2		ENSP00000450821
DLK1	ENST00000392848.9	c.218A>T	p.Gln73Leu	missense_variant	5/6	4		ENSP00000376589

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2837 AN: 152116 Hom.: 81 Cov.: 32

Gnomad AFR AF: 0.0649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00470 AC: 1182 AN: 251398 Hom.: 28 AF XY: 0.00338 AC XY: 459 AN XY: 135882

Gnomad AFR exome AF: 0.0661

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00180 AC: 2632 AN: 1461818 Hom.: 76 Cov.: 31 AF XY: 0.00157 AC XY: 1141 AN XY: 727212

Gnomad4 AFR exome AF: 0.0664

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.0186 AC: 2838 AN: 152234 Hom.: 81 Cov.: 32 AF XY: 0.0179 AC XY: 1332 AN XY: 74430

Gnomad4 AFR AF: 0.0648

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00282 Hom.: 12

Bravo AF: 0.0210

ESP6500AA AF: 0.0713 AC: 314

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00591 AC: 718

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;D;D;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T;.;T;T;T
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.2	.;M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-6.7	D;D;.;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D;D;.;D;D
Sift4G	Uncertain	0.027	D;D;.;T;D
Polyphen		0.91, 0.99	.;P;P;D;.
Vest4		0.71, 0.67, 0.65
MVP		0.94
MPC		0.65
ClinPred		0.072	T
GERP RS		4.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.65
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34686110; hg19: chr14-101195359; COSMIC: COSV99044498; COSMIC: COSV99044498;