Genetic Variant ARHGDIB:p.Pro26Ser (chr12-14950637-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001175.7(ARHGDIB):c.76C>T(p.Pro26Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000719 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

ARHGDIB
NM_001175.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32

Variant links:

Genes affected

ARHGDIB (HGNC:679): (Rho GDP dissociation inhibitor beta) Members of the Rho (or ARH) protein family (see MIM 165390) and other Ras-related small GTP-binding proteins (see MIM 179520) are involved in diverse cellular events, including cell signaling, proliferation, cytoskeletal organization, and secretion. The GTP-binding proteins are active only in the GTP-bound state. At least 3 classes of proteins tightly regulate cycling between the GTP-bound and GDP-bound states: GTPase-activating proteins (GAPs), guanine nucleotide-releasing factors (GRFs), and GDP-dissociation inhibitors (GDIs). The GDIs, including ARHGDIB, decrease the rate of GDP dissociation from Ras-like GTPases (summary by Scherle et al., 1993 [PubMed 8356058]).[supplied by OMIM, Dec 2010]

ARHGDIB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIB	NM_001175.7 link	c.76C>T	p.Pro26Ser	missense_variant	Exon 2 of 6	ENST00000228945.9	NP_001166.3	P52566A0A024RAS5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGDIB	ENST00000228945.9 link	c.76C>T	p.Pro26Ser	missense_variant	Exon 2 of 6	1	NM_001175.7	ENSP00000228945.4		P52566

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251156

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461744

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33460

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000917

AC:

102

AN:

1111914

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41544

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.76C>T (p.P26S) alteration is located in exon 2 (coding exon 1) of the ARHGDIB gene. This alteration results from a C to T substitution at nucleotide position 76, causing the proline (P) at amino acid position 26 to be replaced by a serine (S). 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

Pathogenic

0.60

BayesDel_addAF

Benign

-0.017

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;D;D;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

.;.;D;D;D;D

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.52

D;D;D;D;D;D

MetaSVM

Uncertain

-0.062

MutationAssessor

Pathogenic

3.5

H;H;H;.;.;.

PhyloP100

5.3

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.9

D;D;D;D;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.011

D;D;D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;.;.;.

Polyphen

0.84

P;P;P;.;.;.

Vest4

0.56

MVP

0.61

MPC

0.48

ClinPred

0.90

GERP RS

5.3

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.69

gMVP

0.47

Mutation Taster

=62/38

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

LitVar

Below is the list of publications found by LitVar for variant 12:14950637 G>A . It may be empty.

chr12-14950637-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over