chr12-57476372-A-C

Variant names:

• chr12-57476372-A-C
• rs11544238
• NM_032496.4:c.1108T>G

Variant summary

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

The NM_032496.4(ARHGAP9):​c.1108T>G​(p.Ser370Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 1,613,282 control chromosomes in the GnomAD database, including 286,440 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.47 (19470 hom., cov: 31)
  • Exomes 𝑓: 0.60 (266970 hom.)
• Consequence: ARHGAP9 NM_032496.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.111
• Publications: 44 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
• trichothiodystrophy 9, nonphotosensitive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• spastic paraplegia 70, autosomal recessive

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7234335E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.632 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.1108T>G	p.Ser370Ala	missense	Exon 8 of 18	NP_115885.2	Q9BRR9-2
	ARHGAP9	NM_001319850.2		c.1108T>G	p.Ser370Ala	missense	Exon 11 of 21	NP_001306779.2	Q9BRR9-1
	ARHGAP9	NM_001080157.2		c.1108T>G	p.Ser370Ala	missense	Exon 7 of 16	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.1108T>G	p.Ser370Ala	missense	Exon 8 of 18	ENSP00000377380.3	Q9BRR9-2
	ARHGAP9	ENST00000393797.7	TSL:1	c.1108T>G	p.Ser370Ala	missense	Exon 11 of 21	ENSP00000377386.3	Q9BRR9-1
	ARHGAP9	ENST00000430041.6	TSL:1	c.556T>G	p.Ser186Ala	missense	Exon 6 of 16	ENSP00000397950.2	Q9BRR9-4

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71421 AN: 151878 Hom.: 19481 Cov.: 31

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.520

GnomAD2 exomes AF: 0.504 AC: 126022 AN: 249864 AF XY: 0.521

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.607

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.505

Gnomad NFE exome AF: 0.631

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.595 AC: 869784 AN: 1461286 Hom.: 266970 Cov.: 61 AF XY: 0.595 AC XY: 432172 AN XY: 726946

African (AFR) AF: 0.185 AC: 6190 AN: 33466

American (AMR) AF: 0.336 AC: 15011 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 15859 AN: 26132

East Asian (EAS) AF: 0.430 AC: 17050 AN: 39682

South Asian (SAS) AF: 0.479 AC: 41296 AN: 86242

European-Finnish (FIN) AF: 0.511 AC: 27220 AN: 53224

Middle Eastern (MID) AF: 0.657 AC: 3775 AN: 5748

European-Non Finnish (NFE) AF: 0.638 AC: 709794 AN: 1111746

Other (OTH) AF: 0.556 AC: 33589 AN: 60364

GnomAD4 genome AF: 0.470 AC: 71409 AN: 151996 Hom.: 19470 Cov.: 31 AF XY: 0.464 AC XY: 34431 AN XY: 74274

African (AFR) AF: 0.198 AC: 8189 AN: 41456

American (AMR) AF: 0.431 AC: 6590 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2121 AN: 3470

East Asian (EAS) AF: 0.346 AC: 1781 AN: 5150

South Asian (SAS) AF: 0.473 AC: 2275 AN: 4808

European-Finnish (FIN) AF: 0.512 AC: 5416 AN: 10570

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.637 AC: 43293 AN: 67952

Other (OTH) AF: 0.514 AC: 1084 AN: 2110

Alfa AF: 0.590 Hom.: 117636

Bravo AF: 0.446

TwinsUK AF: 0.638 AC: 2366

ALSPAC AF: 0.645 AC: 2485

ESP6500AA AF: 0.205 AC: 902

ESP6500EA AF: 0.635 AC: 5463

ExAC AF: 0.507 AC: 61503

Asia WGS AF: 0.393 AC: 1369 AN: 3478

EpiCase AF: 0.646

EpiControl AF: 0.649

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Coronary artery spasm 3, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.62
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.000017	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.11
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.073
Sift	Benign	0.25	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.041
ClinPred		0.0093	T
GERP RS		-3.4
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11544238; hg19: chr12-57870155; COSMIC: COSV57361127; COSMIC: COSV57361127;