rs542278

Variant names:

• chr12-57478937-G-A
• rs542278
• NM_032496.4:c.316+154C>T

Variant summary

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

The NM_032496.4(ARHGAP9):​c.316+154C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 152,064 control chromosomes in the GnomAD database, including 1,995 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 0.16 (1995 hom., cov: 32)
• Consequence: ARHGAP9 NM_032496.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.199
• Publications: 9 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
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

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.316+154C>T		intron	N/A	NP_115885.2	Q9BRR9-2
	ARHGAP9	NM_001319850.2		c.316+154C>T		intron	N/A	NP_001306779.2	Q9BRR9-1
	ARHGAP9	NM_001080157.2		c.316+154C>T		intron	N/A	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.316+154C>T		intron	N/A	ENSP00000377380.3	Q9BRR9-2
	ARHGAP9	ENST00000393797.7	TSL:1	c.316+154C>T		intron	N/A	ENSP00000377386.3	Q9BRR9-1
	ARHGAP9	ENST00000906774.1		c.316+154C>T		intron	N/A	ENSP00000576833.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23813 AN: 151946 Hom.: 1990 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.157 AC: 23839 AN: 152064 Hom.: 1995 Cov.: 32 AF XY: 0.163 AC XY: 12138 AN XY: 74332

African (AFR) AF: 0.183 AC: 7602 AN: 41450

American (AMR) AF: 0.136 AC: 2079 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3468

East Asian (EAS) AF: 0.271 AC: 1399 AN: 5156

South Asian (SAS) AF: 0.154 AC: 739 AN: 4814

European-Finnish (FIN) AF: 0.206 AC: 2181 AN: 10566

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8660 AN: 67992

Other (OTH) AF: 0.140 AC: 295 AN: 2114

Alfa AF: 0.138 Hom.: 563

Bravo AF: 0.153

Asia WGS AF: 0.174 AC: 607 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.2
DANN	Benign	0.25
PhyloP100		0.20
PromoterAI		-0.0032	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs542278;

hg19: chr12-57872720;