rs1266479603

Variant names:

• chr12-57477653-G-A
• rs1266479603
• NM_032496.4:c.562C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-57477653-G-A
• chr12-57477653-G-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.562C>T​(p.Pro188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P188T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARHGAP9 NM_032496.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• 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=0.0803698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP9	NM_032496.4	c.562C>T	p.Pro188Ser	missense_variant	Exon 4 of 18	ENST00000393791.8	NP_115885.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP9	ENST00000393791.8	c.562C>T	p.Pro188Ser	missense_variant	Exon 4 of 18	1	NM_032496.4	ENSP00000377380.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460632 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726674

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111224

Other (OTH) AF: 0.00 AC: 0 AN: 60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.066232), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.7
DANN	Benign	0.76
DEOGEN2	Benign	0.0019	.;.;.;T;.;T;T;T;.;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.78	T;T;T;.;T;T;T;T;T;T;D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.080	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.81	L;L;.;.;.;.;.;.;.;.;.
PhyloP100		1.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.0	N;N;N;.;N;N;N;N;N;N;D
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T;.;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;.;.;T;.;T;T
Polyphen		0.0070	B;.;.;.;.;.;.;.;.;.;.
Vest4		0.15
MutPred		0.19		Gain of catalytic residue at L184 (P = 2e-04);Gain of catalytic residue at L184 (P = 2e-04);.;.;.;.;.;.;.;.;.;
MVP		0.49
MPC		0.078
ClinPred		0.046	T
GERP RS		-1.5
PromoterAI		0.025	Neutral
gMVP		0.19
Mutation Taster		=93/7	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

dbSNP: rs1266479603; hg19: chr12-57871436; COSMIC: COSV100712433; COSMIC: COSV100712433;