8-13499310-T-G

Position:

• chr8-13499310-T-G

Variant summary

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

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. 14/20 in silico tools predict 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 0.85 (55436 hom., cov: 33)
  • Exomes 𝑓: 0.91 (609555 hom.)
• Consequence: DLC1 NM_182643.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.422

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLC1	NM_182643.3	c.762A>C	p.Gln254His	missense_variant	2/18	ENST00000276297.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLC1	ENST00000276297.9	c.762A>C	p.Gln254His	missense_variant	2/18	1	NM_182643.3
DLC1	ENST00000511869.1	c.762A>C	p.Gln254His	missense_variant	2/5	1
DLC1	ENST00000316609.9	c.762A>C	p.Gln254His	missense_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.847 AC: 128661 AN: 151988 Hom.: 55403 Cov.: 33

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

GnomAD3 exomes AF: 0.850 AC: 213377 AN: 251074 Hom.: 92585 AF XY: 0.861 AC XY: 116874 AN XY: 135690

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 SAS exome AF: 0.853

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.: 77 AF XY: 0.910 AC XY: 661591 AN XY: 727162

Gnomad4 AFR exome AF: 0.720

Gnomad4 AMR exome AF: 0.684

Gnomad4 ASJ exome AF: 0.915

Gnomad4 EAS exome AF: 0.623

Gnomad4 SAS exome AF: 0.855

Gnomad4 FIN exome AF: 0.933

Gnomad4 NFE exome AF: 0.939

Gnomad4 OTH exome AF: 0.888

GnomAD4 genome AF: 0.846 AC: 128746 AN: 152106 Hom.: 55436 Cov.: 33 AF XY: 0.843 AC XY: 62677 AN XY: 74376

Gnomad4 AFR AF: 0.728

Gnomad4 AMR AF: 0.762

Gnomad4 ASJ AF: 0.912

Gnomad4 EAS AF: 0.619

Gnomad4 SAS AF: 0.844

Gnomad4 FIN AF: 0.929

Gnomad4 NFE AF: 0.937

Gnomad4 OTH AF: 0.851

Alfa AF: 0.912 Hom.: 117874

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

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2019	This variant is associated with the following publications: (PMID: 26095787) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.090
DANN	Benign	0.82
DEOGEN2	Benign	0.068	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.50	T;.;.
MetaRNN	Benign	0.0000011	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.080
MutPred		0.14		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MPC		0.023
ClinPred		0.0066	T
GERP RS		-5.6
Varity_R		0.065
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs11203495; hg19: chr8-13356819; COSMIC: COSV99362530; COSMIC: COSV99362530;