Genetic Variant NM_001164431.3:c.514C>T (chr20-38627171-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001164431.3(ARHGAP40):c.514C>T(p.Pro172Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,305,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 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: 3.03

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06826562).

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.514C>T	p.Pro172Ser	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.514C>T	p.Pro172Ser	missense	Exon 3 of 15	ENSP00000362442.5	Q5TG30
ARHGAP40	ENST00000906550.1		c.514C>T	p.Pro172Ser	missense	Exon 3 of 13	ENSP00000576609.1
ARHGAP40	ENST00000243967.8	TSL:5	c.175C>T	p.Pro59Ser	missense	Exon 1 of 14	ENSP00000243967.4	H7BXE0

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000840

AC:

AN:

154828

AF XY:

0.0000974

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00153

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:

0.0000173

AC:

AN:

1153102

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

565414

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24418

American (AMR)

AF:

0.00

AC:

AN:

28270

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

15940

East Asian (EAS)

AF:

0.00

AC:

AN:

12844

South Asian (SAS)

AF:

0.00

AC:

AN:

76204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4402

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

920932

Other (OTH)

AF:

0.0000480

AC:

AN:

41636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

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:

0.000174

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000157

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

0.094

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

Eigen

Benign

0.10

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.63

M_CAP

Benign

0.045

MetaRNN

Benign

0.068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

3.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.069

Sift

Benign

0.40

Sift4G

Benign

0.28

Vest4

0.15

MutPred

0.37

Gain of phosphorylation at P119 (P = 0.0323)

MVP

0.19

ClinPred

0.21

GERP RS

4.8

PromoterAI

0.0047

Neutral

(source)

Varity_R

0.11

gMVP

0.60

Mutation Taster

=81/19

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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