NM_032496.4:c.1108T>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.111

Publications

44 publications found

Variant links:

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]

ARHGAP9 links:

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

MARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP9	NM_032496.4 link	c.1108T>G	p.Ser370Ala	missense_variant	Exon 8 of 18	ENST00000393791.8	NP_115885.2	Q9BRR9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP9	ENST00000393791.8 link	c.1108T>G	p.Ser370Ala	missense_variant	Exon 8 of 18	1	NM_032496.4	ENSP00000377380.3		Q9BRR9-2

Frequencies

GnomAD3 genomes

AF:

0.470

AC:

71421

AN:

151878

Hom.:

19481

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.595

AC XY:

432172

AN XY:

726946

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

18988

37977

56965

75954

94942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.470

AC:

71409

AN:

151996

Hom.:

19470

Cov.:

AF XY:

0.464

AC XY:

34431

AN XY:

74274

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1733

3467

5200

6934

8667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Coronary artery spasm 3, susceptibility to

Uncertain:1

Jan 01, 2010

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.16

.;.;.;T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.32

T;T;T;.;T;T

MetaRNN

Benign

0.000017

T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

L;L;.;.;.;.

PhyloP100

-0.11

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.63

N;N;N;.;N;N

REVEL

Benign

0.073

Sift

Benign

0.25

T;T;T;.;T;T

Sift4G

Benign

0.14

T;T;T;T;T;.

Polyphen

0.0

B;.;.;.;.;.

Vest4

0.11

MPC

0.041

ClinPred

0.0093

GERP RS

-3.4

gMVP

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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NM_032496.4:c.1108T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over