14-32092090-T-C

Position:

• chr14-32092090-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001030055.2(ARHGAP5):​c.1421T>C​(p.Val474Ala) 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARHGAP5 NM_001030055.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

Genes affected

ARHGAP5 (HGNC:675): (Rho GTPase activating protein 5) Rho GTPase activating protein 5 negatively regulates RHO GTPases, a family which may mediate cytoskeleton changes by stimulating the hydrolysis of bound GTP. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-32092090-T-C is Pathogenic according to our data. Variant chr14-32092090-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1696854.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15024415). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP5	NM_001030055.2	c.1421T>C	p.Val474Ala	missense_variant	2/7	ENST00000345122.8	NP_001025226.1
ARHGAP5	NM_001173.3	c.1421T>C	p.Val474Ala	missense_variant	2/7		NP_001164.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP5	ENST00000345122.8	c.1421T>C	p.Val474Ala	missense_variant	2/7	5	NM_001030055.2	ENSP00000371897	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0113 Hom.: 0

ExAC AF: 0.00147 AC: 179

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary artery atresia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Henan Key Laboratory of Chronic Disease Management, Central China Fuwai Hospital of Zhengzhou University, Fuwai Central China Cardiovascular Hospital & Central China Branch of National Center for Cardiovascular Diseases

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D;.;D
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.5	L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.93	P;P;.;P
Vest4		0.77
MVP		0.68
MPC		0.69
ClinPred		0.24	T
GERP RS		6.0
Varity_R		0.59
gMVP		0.56

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: rs200111638; hg19: chr14-32561296; COSMIC: COSV61534127; COSMIC: COSV61534127;