12-57475389-G-A

Variant summary

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

The NM_032496.4(ARHGAP9):c.1454C>T(p.Pro485Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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: 6.9e-7 (0 hom.)
• Consequence: ARHGAP9 NM_032496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

ARHGAP9 (HGNC:14130): (Rho GTPase activating protein 9) This gene encodes a member of the Rho-GAP family of GTPase activating proteins. The protein has substantial GAP activity towards several Rho-family GTPases in vitro, converting them to an inactive GDP-bound state. It is implicated in regulating adhesion of hematopoietic cells to the extracellular matrix. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.1271488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP9	NM_032496.4	c.1454C>T	p.Pro485Leu	missense_variant	12/18	ENST00000393791.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP9	ENST00000393791.8	c.1454C>T	p.Pro485Leu	missense_variant	12/18	1	NM_032496.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442686 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 715946

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: 0.00

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

Sep 16, 2021

The c.1454C>T (p.P485L) alteration is located in exon 12 (coding exon 11) of the ARHGAP9 gene. This alteration results from a C to T substitution at nucleotide position 1454, causing the proline (P) at amino acid position 485 to be replaced by a leucine (L). 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	0.082
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Benign	0.85
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	D;D;T;.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.56	D;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.21	N;N;N;.;N
REVEL	Benign	0.10
Sift	Benign	0.30	T;T;T;.;T
Sift4G	Benign	0.49	T;T;T;T;T
Polyphen		0.017	B;.;.;.;.
Vest4		0.078
MVP		0.45
MPC		1.3
ClinPred		0.29	T
GERP RS		5.0
gMVP		0.63

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: chr12-57869172;