rs511752

Variant names:

• chr12-57483373-T-C
• rs511752
• ENST00000393797.7:c.-135+522A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000393797.7(ARHGAP9):​c.-135+522A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,056 control chromosomes in the GnomAD database, including 2,672 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2672 hom., cov: 31)
• Consequence: ARHGAP9 ENST00000393797.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000393797.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP9	NM_001319850.2		c.-135+522A>G		intron	N/A	NP_001306779.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP9	ENST00000393797.7	TSL:1	c.-135+522A>G		intron	N/A	ENSP00000377386.3
	ARHGAP9	ENST00000550288.6	TSL:2	c.-135+522A>G		intron	N/A	ENSP00000473445.2
	MARS1	ENST00000549133.1	TSL:3	n.406-4013T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27135 AN: 151934 Hom.: 2659 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.179 AC: 27181 AN: 152056 Hom.: 2672 Cov.: 31 AF XY: 0.184 AC XY: 13712 AN XY: 74338

African (AFR) AF: 0.246 AC: 10213 AN: 41434

American (AMR) AF: 0.153 AC: 2333 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 661 AN: 3470

East Asian (EAS) AF: 0.275 AC: 1420 AN: 5162

South Asian (SAS) AF: 0.154 AC: 743 AN: 4824

European-Finnish (FIN) AF: 0.207 AC: 2190 AN: 10582

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9017 AN: 67988

Other (OTH) AF: 0.166 AC: 350 AN: 2108

Alfa AF: 0.164 Hom.: 267

Bravo AF: 0.178

Asia WGS AF: 0.180 AC: 630 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.79
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs511752; hg19: chr12-57877156;