12-57477182-C-T

Variant names:

• chr12-57477182-C-T
• NM_032496.4:c.844G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032496.4(ARHGAP9):​c.844G>A​(p.Gly282Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGAP9 NM_032496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.282
• 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: Orphanet, Labcorp Genetics (formerly Invitae)
• severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

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

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• trichothiodystrophy 9, nonphotosensitive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• spastic paraplegia 70, autosomal recessive

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059073508).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032496.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP9	NM_032496.4	MANE Select	c.844G>A	p.Gly282Arg	missense	Exon 5 of 18	NP_115885.2	Q9BRR9-2
	ARHGAP9	NM_001319850.2		c.844G>A	p.Gly282Arg	missense	Exon 8 of 21	NP_001306779.2	Q9BRR9-1
	ARHGAP9	NM_001080157.2		c.844G>A	p.Gly282Arg	missense	Exon 4 of 16	NP_001073626.1	Q9BRR9-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP9	ENST00000393791.8	TSL:1 MANE Select	c.844G>A	p.Gly282Arg	missense	Exon 5 of 18	ENSP00000377380.3	Q9BRR9-2
	ARHGAP9	ENST00000393797.7	TSL:1	c.844G>A	p.Gly282Arg	missense	Exon 8 of 21	ENSP00000377386.3	Q9BRR9-1
	ARHGAP9	ENST00000430041.6	TSL:1	c.292G>A	p.Gly98Arg	missense	Exon 3 of 16	ENSP00000397950.2	Q9BRR9-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460634 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726542

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111352

Other (OTH) AF: 0.0000166 AC: 1 AN: 60338

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.64
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.28
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.024
Sift	Benign	0.45	T
Sift4G	Benign	0.46	T
Polyphen		0.078	B
Vest4		0.14
MutPred		0.27		Gain of catalytic residue at L287 (P = 6e-04)
MVP		0.35
MPC		0.054
ClinPred		0.29	T
GERP RS		0.93
gMVP		0.37
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr12-57870965; COSMIC: COSV57362224; COSMIC: COSV57362224;