11-100961716-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152432.4(ARHGAP42):c.1333A>G(p.Ile445Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGAP42 NM_152432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

Genes affected

ARHGAP42 (HGNC:26545): (Rho GTPase activating protein 42) This gene encodes a Rho GTPase-activating protein (RhoGAP), and member of the GRAF or BAR-PH family of proteins. Expression of this gene is enriched in vascular smooth muscle cells and the encoded protein inhibits RhoA activity to regulate vascular tone and control blood pressure. A mutation in the first intron of this gene modulates its expression and is associated with reduced blood pressure in human patients with borderline hypertension. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07112044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP42	NM_152432.4	c.1333A>G	p.Ile445Val	missense_variant	15/24	ENST00000298815.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP42	ENST00000298815.13	c.1333A>G	p.Ile445Val	missense_variant	15/24	5	NM_152432.4	P1
ARHGAP42	ENST00000524892.7	c.1231A>G	p.Ile411Val	missense_variant	14/23	5
ARHGAP42	ENST00000529535.1	c.205A>G	p.Ile69Val	missense_variant, NMD_transcript_variant	3/13	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399482 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 690222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The c.1333A>G (p.I445V) alteration is located in exon 15 (coding exon 15) of the ARHGAP42 gene. This alteration results from a A to G substitution at nucleotide position 1333, causing the isoleucine (I) at amino acid position 445 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	19
Dann	Benign	0.48
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.026
Sift	Benign	1.0	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0010	.;B
Vest4		0.092
MutPred		0.47		.;Gain of disorder (P = 0.2309);
MVP		0.092
ClinPred		0.14	T
GERP RS		2.1
Varity_R		0.024
gMVP		0.16

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: rs1284109157; hg19: chr11-100832447;