Genetic Variant ARHGAP40:p.Thr273Met (chr20-38634654-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001164431.3(ARHGAP40):c.818C>T(p.Thr273Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,305,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ARHGAP40
NM_001164431.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.77

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3041396).

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.818C>T	p.Thr273Met	missense	Exon 6 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.818C>T	p.Thr273Met	missense	Exon 6 of 15	ENSP00000362442.5	Q5TG30
ARHGAP40	ENST00000906550.1		c.593C>T	p.Thr198Met	missense	Exon 4 of 13	ENSP00000576609.1
ARHGAP40	ENST00000243967.8	TSL:5	c.479C>T	p.Thr160Met	missense	Exon 4 of 14	ENSP00000243967.4	H7BXE0

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.00000639

AC:

AN:

156560

AF XY:

0.0000121

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000121

AC:

AN:

1153100

Hom.:

Cov.:

AF XY:

0.0000106

AC XY:

AN XY:

565414

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24418

American (AMR)

AF:

0.0000354

AC:

AN:

28270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15940

East Asian (EAS)

AF:

0.00

AC:

AN:

12844

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28460

Middle Eastern (MID)

AF:

0.000227

AC:

AN:

4404

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

920930

Other (OTH)

AF:

0.00

AC:

AN:

41634

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000189

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

0.29

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.75

M_CAP

Benign

0.062

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.2

PhyloP100

2.8

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-5.4

REVEL

Benign

0.065

Sift

Uncertain

0.014

Sift4G

Pathogenic

0.0010

Vest4

0.26

MutPred

0.39

Gain of MoRF binding (P = 0.0776)

MVP

0.17

ClinPred

0.94

GERP RS

2.0

Varity_R

0.062

gMVP

0.68

Mutation Taster

=91/9

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over