rs201853667

Variant names:

• chr12-57476616-C-A
• rs201853667
• NM_032496.4:c.999G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-57476616-C-A
• chr12-57476616-C-G
• chr12-57476616-C-T

Variant summary

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

The NM_032496.4(ARHGAP9):​c.999G>T​(p.Lys333Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ARHGAP9 NM_032496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.784
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP9	NM_032496.4	c.999G>T	p.Lys333Asn	missense_variant	Exon 7 of 18	ENST00000393791.8	NP_115885.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP9	ENST00000393791.8	c.999G>T	p.Lys333Asn	missense_variant	Exon 7 of 18	1	NM_032496.4	ENSP00000377380.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461878 Hom.: 0 Cov.: 40 AF XY: 0.0000110 AC XY: 8 AN XY: 727244

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000244 Hom.: 0

Bravo AF: 0.00000378

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

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.999G>T (p.K333N) alteration is located in exon 7 (coding exon 6) of the ARHGAP9 gene. This alteration results from a G to T substitution at nucleotide position 999, causing the lysine (K) at amino acid position 333 to be replaced by an asparagine (N). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;.;.;D;.;D;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Uncertain	2.9	M;M;.;.;.;.;.
PhyloP100		0.78
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.8	D;D;D;.;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.68
MutPred		0.49		Loss of methylation at K333 (P = 0.0102);Loss of methylation at K333 (P = 0.0102);.;.;.;.;.;
MVP		0.91
MPC		0.28
ClinPred		0.99	D
GERP RS		1.7
gMVP		0.71
Mutation Taster		=77/23	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: rs201853667; hg19: chr12-57870399;