chr8-13499310-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182643.3(DLC1):c.762A>C(p.Gln254His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 1,613,842 control chromosomes in the GnomAD database, including 664,991 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q254E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.85 ( 55436 hom., cov: 33)

Exomes 𝑓: 0.91 ( 609555 hom. )

Consequence

DLC1
NM_182643.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.422

Publications

24 publications found

Variant links:

Genes affected

DLC1 (HGNC:2897): (DLC1 Rho GTPase activating protein) This gene encodes a GTPase-activating protein (GAP) that is a member of the rhoGAP family of proteins which play a role in the regulation of small GTP-binding proteins. GAP family proteins participate in signaling pathways that regulate cell processes involved in cytoskeletal changes. This gene functions as a tumor suppressor gene in a number of common cancers, including prostate, lung, colorectal, and breast cancers. Multiple transcript variants due to alternative promoters and alternative splicing have been found for this gene.[provided by RefSeq, Apr 2010]

DLC1 Gene-Disease associations (from GenCC):

congenital heart defects, multiple types
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
colorectal cancer
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

DLC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0988842E-6).

BP6

Variant 8-13499310-T-G is Benign according to our data. Variant chr8-13499310-T-G is described in ClinVar as Benign. ClinVar VariationId is 1222558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182643.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLC1	NM_182643.3	MANE Select	c.762A>C	p.Gln254His	missense	Exon 2 of 18	NP_872584.2
DLC1	NM_001348081.2		c.762A>C	p.Gln254His	missense	Exon 2 of 18	NP_001335010.1
DLC1	NM_001413124.1		c.762A>C	p.Gln254His	missense	Exon 2 of 18	NP_001400053.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLC1	ENST00000276297.9	TSL:1 MANE Select	c.762A>C	p.Gln254His	missense	Exon 2 of 18	ENSP00000276297.4
DLC1	ENST00000511869.1	TSL:1	c.762A>C	p.Gln254His	missense	Exon 2 of 5	ENSP00000425878.1
DLC1	ENST00000941272.1		c.762A>C	p.Gln254His	missense	Exon 3 of 19	ENSP00000611331.1

Frequencies

GnomAD3 genomes

AF:

0.847

AC:

128661

AN:

151988

Hom.:

55403

Cov.:

show subpopulations

Gnomad AFR

AF:

0.728

Gnomad AMI

AF:

0.974

Gnomad AMR

AF:

0.762

Gnomad ASJ

AF:

0.912

Gnomad EAS

AF:

0.619

Gnomad SAS

AF:

0.842

Gnomad FIN

AF:

0.929

Gnomad MID

AF:

0.904

Gnomad NFE

AF:

0.937

Gnomad OTH

AF:

0.850

GnomAD2 exomes

AF:

0.850

AC:

213377

AN:

251074

AF XY:

0.861

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.678

Gnomad ASJ exome

AF:

0.915

Gnomad EAS exome

AF:

0.602

Gnomad FIN exome

AF:

0.931

Gnomad NFE exome

AF:

0.937

Gnomad OTH exome

AF:

0.871

GnomAD4 exome

AF:

0.910

AC:

1330008

AN:

1461736

Hom.:

609555

Cov.:

AF XY:

0.910

AC XY:

661591

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.720

AC:

24107

AN:

33464

American (AMR)

AF:

0.684

AC:

30573

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.915

AC:

23912

AN:

26128

East Asian (EAS)

AF:

0.623

AC:

24731

AN:

39698

South Asian (SAS)

AF:

0.855

AC:

73742

AN:

86256

European-Finnish (FIN)

AF:

0.933

AC:

49794

AN:

53388

Middle Eastern (MID)

AF:

0.915

AC:

5276

AN:

5768

European-Non Finnish (NFE)

AF:

0.939

AC:

1044263

AN:

1111960

Other (OTH)

AF:

0.888

AC:

53610

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

7053

14106

21159

28212

35265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21488

42976

64464

85952

107440

<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:

0.846

AC:

128746

AN:

152106

Hom.:

55436

Cov.:

AF XY:

0.843

AC XY:

62677

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.728

AC:

30182

AN:

41462

American (AMR)

AF:

0.762

AC:

11647

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.912

AC:

3163

AN:

3468

East Asian (EAS)

AF:

0.619

AC:

3190

AN:

5152

South Asian (SAS)

AF:

0.844

AC:

4072

AN:

4826

European-Finnish (FIN)

AF:

0.929

AC:

9848

AN:

10604

Middle Eastern (MID)

AF:

0.918

AC:

268

AN:

292

European-Non Finnish (NFE)

AF:

0.937

AC:

63693

AN:

67990

Other (OTH)

AF:

0.851

AC:

1795

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

909

1818

2728

3637

4546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

880

1760

2640

3520

4400

<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:

0.893

Hom.:

175039

Bravo

AF:

0.825

TwinsUK

AF:

0.947

AC:

3511

ALSPAC

AF:

0.935

AC:

3605

ESP6500AA

AF:

0.736

AC:

3245

ESP6500EA

AF:

0.930

AC:

7997

ExAC

AF:

0.856

AC:

103897

Asia WGS

AF:

0.765

AC:

2662

AN:

3478

EpiCase

AF:

0.935

EpiControl

AF:

0.931

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.090

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.068

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0000011

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

PhyloP100

-0.42

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.44

REVEL

Benign

0.012

Sift

Benign

0.21

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.080

MutPred

0.14

Gain of sheet (P = 0.0827)

MPC

0.023

ClinPred

0.0066

GERP RS

-5.6

PromoterAI

0.016

Neutral

(source)

Varity_R

0.065

gMVP

0.13

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over