Genetic Variant ARHGAP40:p.Arg163Cys (chr20-38627144-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164431.3(ARHGAP40):c.487C>T(p.Arg163Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 1,305,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ARHGAP40
NM_001164431.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.338

Publications

0 publications found

Variant links:

Genes affected

ARHGAP40 (HGNC:16226): (Rho GTPase activating protein 40) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of actin filament polymerization and regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ARHGAP40 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.117325276).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164431.3. 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
	ARHGAP40	NM_001164431.3	MANE Select	c.487C>T	p.Arg163Cys	missense	Exon 3 of 15	NP_001157903.2	Q5TG30

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGAP40	ENST00000373345.9	TSL:5 MANE Select	c.487C>T	p.Arg163Cys	missense	Exon 3 of 15	ENSP00000362442.5	Q5TG30
ARHGAP40	ENST00000906550.1		c.487C>T	p.Arg163Cys	missense	Exon 3 of 13	ENSP00000576609.1
ARHGAP40	ENST00000243967.8	TSL:5	c.148C>T	p.Arg50Cys	missense	Exon 1 of 14	ENSP00000243967.4	H7BXE0

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000387

AC:

AN:

154940

AF XY:

0.0000365

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000367

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000333

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1153102

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

565412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24416

American (AMR)

AF:

0.00

AC:

AN:

28270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15942

East Asian (EAS)

AF:

0.000545

AC:

AN:

12844

South Asian (SAS)

AF:

0.00

AC:

AN:

76204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4404

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

920936

Other (OTH)

AF:

0.0000240

AC:

AN:

41634

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000192

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.10

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.75

M_CAP

Benign

0.024

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.34

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.041

Sift

Uncertain

0.0020

Sift4G

Benign

0.12

Vest4

0.14

MutPred

0.52

Loss of MoRF binding (P = 0.0115)

MVP

0.37

ClinPred

0.13

GERP RS

0.36

PromoterAI

-0.0090

Neutral

(source)

Varity_R

0.16

gMVP

0.50

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over