Genetic Variant ARHGDIB:p.Lys135Thr (chr12-14944778-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001175.7(ARHGDIB):c.404A>C(p.Lys135Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ARHGDIB
NM_001175.7 missense, splice_region

Scores

Splicing: ADA: 0.0002526

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.85

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3446225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIB	NM_001175.7 link	c.404A>C	p.Lys135Thr	missense_variant, splice_region_variant	Exon 5 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.404A>C	p.Lys135Thr	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_001175.7	ENSP00000228945.4		P52566

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

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:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460384

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726470

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:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404A>C (p.K135T) alteration is located in exon 5 (coding exon 4) of the ARHGDIB gene. This alteration results from a A to C substitution at nucleotide position 404, causing the lysine (K) at amino acid position 135 to be replaced by a threonine (T). 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

0.70

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D;D;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.88

.;.;D;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.8

L;L;L;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Benign

0.20

Sift

Benign

0.17

T;T;T;T

Sift4G

Benign

0.17

T;T;T;.

Polyphen

0.23

B;B;B;.

Vest4

0.28

MutPred

0.57

Gain of catalytic residue at V134 (P = 0);Gain of catalytic residue at V134 (P = 0);Gain of catalytic residue at V134 (P = 0);Gain of catalytic residue at V134 (P = 0);

MVP

0.64

MPC

0.21

ClinPred

0.71

GERP RS

3.3

Varity_R

0.20

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.010

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