Genetic Variant DLK1:p.Ile188Ile (chr14-100734308-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_003836.7(DLK1):c.564T>C(p.Ile188Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 1,613,058 control chromosomes in the GnomAD database, including 252,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.62 ( 30798 hom., cov: 33)

Exomes 𝑓: 0.54 ( 221227 hom. )

Consequence

DLK1
NM_003836.7 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.449

Publications

41 publications found

Variant links:

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]

DLK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 14-100734308-T-C is Benign according to our data. Variant chr14-100734308-T-C is described in ClinVar as Benign. ClinVar VariationId is 3059696.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.449 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7 link	c.564T>C	p.Ile188Ile	synonymous_variant	Exon 5 of 5	ENST00000341267.9	NP_003827.4
DLK1	NM_001317172.2 link	c.564T>C	p.Ile188Ile	synonymous_variant	Exon 5 of 6		NP_001304101.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9 link	c.564T>C	p.Ile188Ile	synonymous_variant	Exon 5 of 5	1	NM_003836.7	ENSP00000340292.4
DLK1	ENST00000331224.10 link	c.564T>C	p.Ile188Ile	synonymous_variant	Exon 5 of 6	1		ENSP00000331081.6

Frequencies

GnomAD3 genomes

AF:

0.621

AC:

94432

AN:

151990

Hom.:

30742

Cov.:

show subpopulations

Gnomad AFR

AF:

0.738

Gnomad AMI

AF:

0.470

Gnomad AMR

AF:

0.658

Gnomad ASJ

AF:

0.552

Gnomad EAS

AF:

0.996

Gnomad SAS

AF:

0.651

Gnomad FIN

AF:

0.687

Gnomad MID

AF:

0.491

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.596

GnomAD2 exomes

AF:

0.629

AC:

157523

AN:

250360

AF XY:

0.616

show subpopulations

Gnomad AFR exome

AF:

0.745

Gnomad AMR exome

AF:

0.766

Gnomad ASJ exome

AF:

0.550

Gnomad EAS exome

AF:

0.998

Gnomad FIN exome

AF:

0.681

Gnomad NFE exome

AF:

0.507

Gnomad OTH exome

AF:

0.576

GnomAD4 exome

AF:

0.539

AC:

787008

AN:

1460952

Hom.:

221227

Cov.:

AF XY:

0.539

AC XY:

392117

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.752

AC:

25187

AN:

33476

American (AMR)

AF:

0.751

AC:

33596

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

14336

AN:

26122

East Asian (EAS)

AF:

0.999

AC:

39648

AN:

39696

South Asian (SAS)

AF:

0.634

AC:

54717

AN:

86252

European-Finnish (FIN)

AF:

0.672

AC:

35345

AN:

52610

Middle Eastern (MID)

AF:

0.526

AC:

3035

AN:

5768

European-Non Finnish (NFE)

AF:

0.492

AC:

546869

AN:

1111938

Other (OTH)

AF:

0.568

AC:

34275

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

23904

47808

71712

95616

119520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16212

32424

48636

64848

81060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.622

AC:

94548

AN:

152106

Hom.:

30798

Cov.:

AF XY:

0.633

AC XY:

47033

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.739

AC:

30647

AN:

41484

American (AMR)

AF:

0.659

AC:

10073

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.552

AC:

1914

AN:

3470

East Asian (EAS)

AF:

0.996

AC:

5136

AN:

5158

South Asian (SAS)

AF:

0.650

AC:

3134

AN:

4822

European-Finnish (FIN)

AF:

0.687

AC:

7278

AN:

10594

Middle Eastern (MID)

AF:

0.497

AC:

146

AN:

294

European-Non Finnish (NFE)

AF:

0.508

AC:

34523

AN:

67970

Other (OTH)

AF:

0.601

AC:

1269

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1742

3484

5227

6969

8711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.545

Hom.:

70596

Bravo

AF:

0.624

Asia WGS

AF:

0.854

AC:

2967

AN:

3478

EpiCase

AF:

0.490

EpiControl

AF:

0.489

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DLK1-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

3.0

(source)

DANN

Benign

0.78

PhyloP100

-0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over