Variant 11-100859615-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP4

The NM_152432.4(ARHGAP42):c.374G>A(p.Gly125Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,498,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

ARHGAP42
NM_152432.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.98

Variant links:

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]

ARHGAP42 links:

ARHGAP42 (HGNC:):

ARHGAP42 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PrimateAI, PROVEAN [when max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.42361543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP42	NM_152432.4 linkuse as main transcript	c.374G>A	p.Gly125Asp	missense_variant	4/24	ENST00000298815.13	NP_689645.2	A6NI28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP42	ENST00000298815.13 linkuse as main transcript	c.374G>A	p.Gly125Asp	missense_variant	4/24	5	NM_152432.4	ENSP00000298815.7		A6NI28

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000259

AC:

AN:

115616

Hom.:

AF XY:

0.0000162

AC XY:

AN XY:

61844

show subpopulations

Gnomad AFR exome

AF:

0.000401

Gnomad AMR exome

AF:

0.0000654

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000594

AC:

AN:

1346716

Hom.:

Cov.:

AF XY:

0.00000604

AC XY:

AN XY:

662108

show subpopulations

Gnomad4 AFR exome

AF:

0.000174

Gnomad4 AMR exome

AF:

0.0000365

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:

9.47e-7

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2024

The c.374G>A (p.G125D) alteration is located in exon 4 (coding exon 4) of the ARHGAP42 gene. This alteration results from a G to A substitution at nucleotide position 374, causing the glycine (G) at amino acid position 125 to be replaced by an aspartic acid (D). 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

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.043

.;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.42

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.8

.;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

.;D

Vest4

0.53

MVP

0.28

ClinPred

0.65

GERP RS

5.7

Varity_R

0.90

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over