rs3816747

Positions:

• chr8-13499293-G-A

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.779C>T​(p.Thr260Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.916 in 1,614,014 control chromosomes in the GnomAD database, including 680,659 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 0.89 (60501 hom., cov: 33)
  • Exomes 𝑓: 0.92 (620158 hom.)
• Consequence: DLC1 NM_182643.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09

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=7.642247E-7).
• BP6: Variant 8-13499293-G-A is Benign according to our data. Variant chr8-13499293-G-A is described in ClinVar as [Benign]. Clinvar id is 1246243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLC1	NM_182643.3	c.779C>T	p.Thr260Ile	missense_variant	2/18	ENST00000276297.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLC1	ENST00000276297.9	c.779C>T	p.Thr260Ile	missense_variant	2/18	1	NM_182643.3
DLC1	ENST00000511869.1	c.779C>T	p.Thr260Ile	missense_variant	2/5	1
DLC1	ENST00000316609.9	c.779C>T	p.Thr260Ile	missense_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.888 AC: 135081 AN: 152128 Hom.: 60458 Cov.: 33

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.974

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.913

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.938

Gnomad OTH AF: 0.883

GnomAD3 exomes AF: 0.869 AC: 218119 AN: 251102 Hom.: 96536 AF XY: 0.880 AC XY: 119424 AN XY: 135706

Gnomad AFR exome AF: 0.862

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.916

Gnomad EAS exome AF: 0.602

Gnomad SAS exome AF: 0.917

Gnomad FIN exome AF: 0.931

Gnomad NFE exome AF: 0.939

Gnomad OTH exome AF: 0.883

GnomAD4 exome AF: 0.918 AC: 1342592 AN: 1461768 Hom.: 620158 Cov.: 69 AF XY: 0.920 AC XY: 668779 AN XY: 727194

Gnomad4 AFR exome AF: 0.864

Gnomad4 AMR exome AF: 0.693

Gnomad4 ASJ exome AF: 0.916

Gnomad4 EAS exome AF: 0.623

Gnomad4 SAS exome AF: 0.916

Gnomad4 FIN exome AF: 0.933

Gnomad4 NFE exome AF: 0.940

Gnomad4 OTH exome AF: 0.904

GnomAD4 genome AF: 0.888 AC: 135182 AN: 152246 Hom.: 60501 Cov.: 33 AF XY: 0.884 AC XY: 65787 AN XY: 74430

Gnomad4 AFR AF: 0.862

Gnomad4 AMR AF: 0.781

Gnomad4 ASJ AF: 0.913

Gnomad4 EAS AF: 0.619

Gnomad4 SAS AF: 0.910

Gnomad4 FIN AF: 0.929

Gnomad4 NFE AF: 0.938

Gnomad4 OTH AF: 0.885

Alfa AF: 0.917 Hom.: 159255

Bravo AF: 0.871

TwinsUK AF: 0.947 AC: 3511

ALSPAC AF: 0.936 AC: 3606

ESP6500AA AF: 0.865 AC: 3813

ESP6500EA AF: 0.933 AC: 8024

ExAC AF: 0.878 AC: 106560

Asia WGS AF: 0.810 AC: 2819 AN: 3478

EpiCase AF: 0.937

EpiControl AF: 0.933

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	Invitae	Jan 30, 2024	- -
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	0.064
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.011
DANN	Benign	0.70
DEOGEN2	Benign	0.039	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.14	T;.;.
MetaRNN	Benign	7.6e-7	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.2	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.037
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.067
MPC		0.024
ClinPred		0.039	T
GERP RS		-10
Varity_R		0.035
gMVP		0.037

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: rs3816747; hg19: chr8-13356802; COSMIC: COSV52312112; COSMIC: COSV52312112;