dbSNP rs2278945: DLC1:c.1315-36340G>A (chr8-13341642-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_182643.3(DLC1):c.1315-36340G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 151,934 control chromosomes in the GnomAD database, including 18,573 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 18572 hom., cov: 31)

Exomes 𝑓: 0.32 ( 1 hom. )

Consequence

DLC1
NM_182643.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.65

Publications

6 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:

ENSG00000253932 (HGNC:):

ENSG00000253932 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLC1	NM_182643.3 link	c.1315-36340G>A		intron_variant	Intron 4 of 17	ENST00000276297.9	NP_872584.2	Q96QB1-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLC1	ENST00000276297.9 link	c.1315-36340G>A	intron_variant	Intron 4 of 17	1	NM_182643.3	ENSP00000276297.4	Q96QB1-2
DLC1	ENST00000511869.1 link	c.1315-36340G>A	intron_variant	Intron 4 of 4	1		ENSP00000425878.1	Q96QB1-5
ENSG00000253932	ENST00000523495.1 link	n.2376C>T	non_coding_transcript_exon_variant	Exon 2 of 2	5
DLC1	ENST00000316609.9 link	c.1315-36340G>A	intron_variant	Intron 4 of 5	2		ENSP00000321034.5	Q96QB1-3

Frequencies

GnomAD3 genomes

AF:

0.487

AC:

73965

AN:

151794

Hom.:

18573

Cov.:

show subpopulations

Gnomad AFR

AF:

0.361

Gnomad AMI

AF:

0.472

Gnomad AMR

AF:

0.586

Gnomad ASJ

AF:

0.479

Gnomad EAS

AF:

0.525

Gnomad SAS

AF:

0.521

Gnomad FIN

AF:

0.608

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.519

Gnomad OTH

AF:

0.501

GnomAD4 exome

AF:

0.318

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.278

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000199620), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.365

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

0.487

AC:

73993

AN:

151912

Hom.:

18572

Cov.:

AF XY:

0.494

AC XY:

36655

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.360

AC:

14921

AN:

41394

American (AMR)

AF:

0.586

AC:

8945

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.479

AC:

1660

AN:

3468

East Asian (EAS)

AF:

0.525

AC:

2709

AN:

5162

South Asian (SAS)

AF:

0.520

AC:

2502

AN:

4816

European-Finnish (FIN)

AF:

0.608

AC:

6414

AN:

10542

Middle Eastern (MID)

AF:

0.428

AC:

125

AN:

292

European-Non Finnish (NFE)

AF:

0.518

AC:

35233

AN:

67956

Other (OTH)

AF:

0.499

AC:

1055

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1893

3785

5678

7570

9463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.505

Hom.:

19980

Bravo

AF:

0.482

Asia WGS

AF:

0.498

AC:

1735

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.11

(source)

DANN

Benign

0.81

PhyloP100

-2.6

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

Computational scores

Splicing

Publications

Other links and lift over