dbSNP rs3764653: ARHGAP45:p.Leu138Met (chr19-1068735-T-A) – 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_012292.5(ARHGAP45):c.412T>A(p.Leu138Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L138L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

ARHGAP45
NM_012292.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.63

Publications

17 publications found

Variant links:

Genes affected

ARHGAP45 (HGNC:17102): (Rho GTPase activating protein 45) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARHGAP45 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=0.15594774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012292.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGAP45	NM_012292.5	MANE Select	c.412T>A	p.Leu138Met	missense	Exon 2 of 23	NP_036424.2
ARHGAP45	NM_001258328.4		c.460T>A	p.Leu154Met	missense	Exon 2 of 23	NP_001245257.1
ARHGAP45	NM_001321232.2		c.424T>A	p.Leu142Met	missense	Exon 2 of 23	NP_001308161.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARHGAP45	ENST00000313093.7	TSL:1 MANE Select	c.412T>A	p.Leu138Met	missense	Exon 2 of 23	ENSP00000316772.2
ARHGAP45	ENST00000586866.5	TSL:1	c.424T>A	p.Leu142Met	missense	Exon 2 of 23	ENSP00000468615.1
ARHGAP45	ENST00000590214.5	TSL:5	c.493T>A	p.Leu165Met	missense	Exon 2 of 23	ENSP00000466401.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151476

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73912

African (AFR)

AF:

0.00

AC:

AN:

41160

American (AMR)

AF:

0.00

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67838

Other (OTH)

AF:

0.00

AC:

AN:

2080

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

0.010

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.77

M_CAP

Benign

0.057

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.8

PhyloP100

1.6

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.85

REVEL

Benign

0.062

Sift

Uncertain

0.015

Sift4G

Benign

0.16

Polyphen

0.98

Vest4

0.36

MutPred

0.24

Gain of catalytic residue at L138 (P = 0.0309)

MVP

0.29

MPC

1.5

ClinPred

0.82

GERP RS

2.1

Varity_R

0.11

gMVP

0.31

Mutation Taster

=90/10

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over