chr12-14950538-C-T

Variant names:

• chr12-14950538-C-T
• NM_001175.7:c.175G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001175.7(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. 14/21 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: 6.8e-7 (0 hom.)
• Consequence: ARHGDIB NM_001175.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19965562).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001175.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGDIB	NM_001175.7	MANE Select	c.175G>A	p.Val59Met	missense	Exon 2 of 6	NP_001166.3	P52566
	ARHGDIB	NM_001321420.2		c.175G>A	p.Val59Met	missense	Exon 3 of 7	NP_001308349.1	P52566
	ARHGDIB	NM_001321421.2		c.175G>A	p.Val59Met	missense	Exon 2 of 6	NP_001308350.1	P52566

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGDIB	ENST00000228945.9	TSL:1 MANE Select	c.175G>A	p.Val59Met	missense	Exon 2 of 6	ENSP00000228945.4	P52566
	ARHGDIB	ENST00000541546.5	TSL:5	c.175G>A	p.Val59Met	missense	Exon 3 of 7	ENSP00000440560.1	P52566
	ARHGDIB	ENST00000541644.5	TSL:5	c.175G>A	p.Val59Met	missense	Exon 2 of 6	ENSP00000444860.1	P52566

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

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111070

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.069
Sift	Benign	0.12	T
Sift4G	Uncertain	0.040	D
Polyphen		0.057	B
Vest4		0.46
MutPred		0.34		Gain of catalytic residue at K63 (P = 0)
MVP		0.38
MPC		0.16
ClinPred		0.34	T
GERP RS		3.3
PromoterAI		0.018	Neutral
Varity_R		0.19
gMVP		0.27
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

hg19: chr12-15103472;