1-161048113-G-A

Variant summary

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

The NM_001025598.2(ARHGAP30):c.2908C>T(p.Arg970Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ARHGAP30 NM_001025598.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.486

Genes affected

ARHGAP30 (HGNC:27414): (Rho GTPase activating protein 30) Predicted to enable GTPase activator activity. Predicted to be involved in small GTPase mediated signal transduction. Located in intracellular membrane-bounded organelle. [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=0.26618618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP30	NM_001025598.2	c.2908C>T	p.Arg970Trp	missense_variant	12/12	ENST00000368013.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP30	ENST00000368013.8	c.2908C>T	p.Arg970Trp	missense_variant	12/12	2	NM_001025598.2	P2
ARHGAP30	ENST00000368015.1	c.2377C>T	p.Arg793Trp	missense_variant	8/8	5
ARHGAP30	ENST00000368016.7	c.2275C>T	p.Arg759Trp	missense_variant	13/13	5		A2
ARHGAP30	ENST00000461003.5	n.3690C>T		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250950 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461854 Hom.: 0 Cov.: 44 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Jun 07, 2023

The c.2908C>T (p.R970W) alteration is located in exon 12 (coding exon 12) of the ARHGAP30 gene. This alteration results from a C to T substitution at nucleotide position 2908, causing the arginine (R) at amino acid position 970 to be replaced by a tryptophan (W). 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	0.24
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	0.026
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.75	D;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.40
MutPred		0.32		.;Loss of methylation at R970 (P = 0.0291);.;
MVP		0.40
MPC		0.24
ClinPred		0.89	D
GERP RS		1.3
Varity_R		0.29
gMVP		0.20

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: rs747453785; hg19: chr1-161017903; COSMIC: COSV63515201; COSMIC: COSV63515201;