chrX-131084374-G-A

Position:

• chrX-131084374-G-A

Variant summary

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

The NM_144967.4(ARHGAP36):​c.715G>A​(p.Val239Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,075 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ARHGAP36 NM_144967.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

ARHGAP36 (HGNC:26388): (Rho GTPase activating protein 36) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of catalytic activity and signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3626808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP36	NM_144967.4	c.715G>A	p.Val239Ile	missense_variant	5/12	ENST00000276211.10
ARHGAP36	NM_001282607.2	c.679G>A	p.Val227Ile	missense_variant	5/12
ARHGAP36	NM_001330651.1	c.307G>A	p.Val103Ile	missense_variant	4/11
ARHGAP36	XM_011531280.2	c.307G>A	p.Val103Ile	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP36	ENST00000276211.10	c.715G>A	p.Val239Ile	missense_variant	5/12	2	NM_144967.4	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095075 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 360685

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

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

Nov 08, 2022

The c.715G>A (p.V239I) alteration is located in exon 5 (coding exon 4) of the ARHGAP36 gene. This alteration results from a G to A substitution at nucleotide position 715, causing the valine (V) at amino acid position 239 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T;.;.;.;.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.79	N;N;N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.063	T;T;D;.;T;T
Sift4G	Uncertain	0.038	D;D;D;.;.;D
Polyphen		0.99	D;D;.;.;D;.
Vest4		0.29
MutPred		0.61		Gain of stability (P = 0.1894);.;.;.;.;.;
MVP		0.23
MPC		1.4
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2079822985; hg19: chrX-130218348;