chr8-13086308-A-G

Position:

• chr8-13086308-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182643.3(DLC1):​c.4448T>C​(p.Met1483Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLC1 NM_182643.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLC1	NM_182643.3	c.4448T>C	p.Met1483Thr	missense_variant	17/18	ENST00000276297.9	NP_872584.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLC1	ENST00000276297.9	c.4448T>C	p.Met1483Thr	missense_variant	17/18	1	NM_182643.3	ENSP00000276297.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.1	L;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.32	B;P;.;.
Vest4		0.82
MutPred		0.80		Loss of sheet (P = 0.0817);.;.;.;
MVP		0.59
MPC		0.13
ClinPred		0.87	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.46
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1817552090; hg19: chr8-12943817; COSMIC: COSV99366341;