Genetic Variant NM_001282290.2:c.2648C>G (chr17-45395478-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001282290.2(ARHGAP27):c.2648C>G(p.Ala883Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A883V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ARHGAP27
NM_001282290.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.46

Publications

3 publications found

Variant links:

Genes affected

ARHGAP27 (HGNC:31813): (Rho GTPase activating protein 27) This gene encodes a member of a large family of proteins that activate Rho-type guanosine triphosphate (GTP) metabolizing enzymes. The encoded protein may pay a role in clathrin-mediated endocytosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2013]

ARHGAP27 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059597075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP27	NM_001282290.2 link	c.2648C>G	p.Ala883Gly	missense_variant	Exon 20 of 20	ENST00000685559.1	NP_001269219.1	Q6ZUM4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP27	ENST00000685559.1 link	c.2648C>G	p.Ala883Gly	missense_variant	Exon 20 of 20		NM_001282290.2	ENSP00000509127.1		Q6ZUM4-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

T;T;.;T;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.49

T;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.060

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.35

.;N;.;.;.

PhyloP100

2.5

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.36

N;N;N;N;N

REVEL

Benign

0.044

Sift

Benign

0.17

T;D;T;T;D

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.031

.;B;.;.;.

Vest4

0.040

MutPred

0.46

.;Loss of stability (P = 0.0641);.;.;.;

MVP

0.30

MPC

0.39

ClinPred

0.16

GERP RS

3.4

Varity_R

0.059

gMVP

0.054

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over