Genetic Variant NM_018460.4:c.368A>C (chr2-143228652-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018460.4(ARHGAP15):c.368A>C(p.Gln123Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,450,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARHGAP15
NM_018460.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.65

Variant links:

Genes affected

ARHGAP15 (HGNC:21030): (Rho GTPase activating protein 15) RHO GTPases (see ARHA; MIM 165390) regulate diverse biologic processes, and their activity is regulated by RHO GTPase-activating proteins (GAPs), such as ARHGAP15 (Seoh et al., 2003 [PubMed 12650940]).[supplied by OMIM, Mar 2008]

ARHGAP15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18622771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP15	NM_018460.4 link	c.368A>C	p.Gln123Pro	missense_variant	Exon 5 of 14	ENST00000295095.11	NP_060930.3	Q53QZ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP15	ENST00000295095.11 link	c.368A>C	p.Gln123Pro	missense_variant	Exon 5 of 14	1	NM_018460.4	ENSP00000295095.6		Q53QZ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245214

Hom.:

AF XY:

0.00000753

AC XY:

AN XY:

132780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721822

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000633

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368A>C (p.Q123P) alteration is located in exon 5 (coding exon 4) of the ARHGAP15 gene. This alteration results from a A to C substitution at nucleotide position 368, causing the glutamine (Q) at amino acid position 123 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.033

T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

0.071

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.65

.;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.15

Sift

Benign

0.28

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.0

.;B

Vest4

0.20

MutPred

0.57

Loss of MoRF binding (P = 0.0688);Loss of MoRF binding (P = 0.0688);

MVP

0.75

MPC

0.066

ClinPred

0.36

GERP RS

4.4

Varity_R

0.15

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over