12-57476616-C-G

Variant names:

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

Variant summary

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

The NM_032496.4(ARHGAP9):​c.999G>C​(p.Lys333Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARHGAP9 NM_032496.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.784

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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>C	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>C	p.Lys333Asn	missense_variant	Exon 7 of 18	1	NM_032496.4	ENSP00000377380.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 40 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

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	0.65	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Uncertain	2.9	M;M;.;.;.;.;.
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

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: chr12-57870399;