chr12-14950538-C-T

Position:

• chr12-14950538-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000228945.9(ARHGDIB):​c.175G>A​(p.Val59Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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: 6.8e-7 (0 hom.)
• Consequence: ARHGDIB ENST00000228945.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

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 (HGNC:):

ACMG classification

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=0.19965562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGDIB	NM_001175.7	c.175G>A	p.Val59Met	missense_variant	2/6	ENST00000228945.9	NP_001166.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGDIB	ENST00000228945.9	c.175G>A	p.Val59Met	missense_variant	2/6	1	NM_001175.7	ENSP00000228945.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460396 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726512

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.175G>A (p.V59M) alteration is located in exon 2 (coding exon 1) of the ARHGDIB gene. This alteration results from a G to A substitution at nucleotide position 175, causing the valine (V) at amino acid position 59 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.29	T;T;T;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.85	.;.;D;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.2	M;M;M;.;.;.
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.12	T;T;T;T;T;T
Sift4G	Uncertain	0.040	D;D;D;.;.;.
Polyphen		0.057	B;B;B;.;.;.
Vest4		0.46
MutPred		0.34		Gain of catalytic residue at K63 (P = 0);Gain of catalytic residue at K63 (P = 0);Gain of catalytic residue at K63 (P = 0);Gain of catalytic residue at K63 (P = 0);Gain of catalytic residue at K63 (P = 0);Gain of catalytic residue at K63 (P = 0);
MVP		0.38
MPC		0.16
ClinPred		0.34	T
GERP RS		3.3
Varity_R		0.19
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-15103472;