11-100961732-A-G

Variant summary

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

The NM_152432.4(ARHGAP42):c.1349A>G(p.Asn450Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ARHGAP42 NM_152432.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.76

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP42	NM_152432.4	c.1349A>G	p.Asn450Ser	missense_variant	15/24	ENST00000298815.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP42	ENST00000298815.13	c.1349A>G	p.Asn450Ser	missense_variant	15/24	5	NM_152432.4	P1
ARHGAP42	ENST00000524892.7	c.1247A>G	p.Asn416Ser	missense_variant	14/23	5
ARHGAP42	ENST00000529535.1	c.221A>G	p.Asn74Ser	missense_variant, NMD_transcript_variant	3/13	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399528 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690230

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 27, 2022

The c.1349A>G (p.N450S) 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 1349, causing the asparagine (N) at amino acid position 450 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.0082
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.12
Sift	Benign	0.72	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.024	.;B
Vest4		0.67
MutPred		0.54		.;Gain of catalytic residue at K451 (P = 0.0609);
MVP		0.088
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.087
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-100832463;