rs774931853

Variant names:

• chr12-57476902-C-A
• rs774931853
• NM_032496.4:c.932G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-57476902-C-A
• chr12-57476902-C-G
• chr12-57476902-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032496.4(ARHGAP9):​c.932G>T​(p.Arg311Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGAP9 NM_032496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.523
• Publications: 0 publications found

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]

MARS1 (HGNC:6898): (methionyl-tRNA synthetase 1) This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. The encoded protein is a component of the multi-tRNA synthetase complex and catalyzes the ligation of methionine to tRNA molecules. [provided by RefSeq, Jan 2011]

MARS1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2U

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal recessive spastic paraplegia type 70

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• spastic paraplegia 70, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• trichothiodystrophy 9, nonphotosensitive

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15110508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP9	NM_032496.4	c.932G>T	p.Arg311Leu	missense_variant	Exon 6 of 18	ENST00000393791.8	NP_115885.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP9	ENST00000393791.8	c.932G>T	p.Arg311Leu	missense_variant	Exon 6 of 18	1	NM_032496.4	ENSP00000377380.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461826 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 28

Alfa AF: 0.0000468 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.932G>T (p.R311L) alteration is located in exon 6 (coding exon 5) of the ARHGAP9 gene. This alteration results from a G to T substitution at nucleotide position 932, causing the arginine (R) at amino acid position 311 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	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.013	.;.;.;T;.;T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.79	T;T;T;.;T;T;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	2.0	M;M;.;.;.;.;.;.
PhyloP100		0.52
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.60	N;N;N;.;N;N;D;N
REVEL	Benign	0.062
Sift	Uncertain	0.027	D;D;D;.;D;T;D;D
Sift4G	Benign	0.38	T;T;T;T;T;.;D;.
Polyphen		0.90	P;.;.;.;.;.;.;.
Vest4		0.46
MutPred		0.36		Gain of catalytic residue at R311 (P = 0.0484);Gain of catalytic residue at R311 (P = 0.0484);.;.;.;.;.;.;
MVP		0.66
MPC		0.066
ClinPred		0.24	T
GERP RS		3.5
gMVP		0.44
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs774931853; hg19: chr12-57870685; COSMIC: COSV57366562; COSMIC: COSV57366562;