Genetic Variant ARHGDIG:p.Pro82Leu (chr16-281917-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001176.4(ARHGDIG):c.245C>T(p.Pro82Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,434,692 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: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ARHGDIG
NM_001176.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.244

Variant links:

Genes affected

ARHGDIG (HGNC:680): (Rho GDP dissociation inhibitor gamma) The GDP-dissociation inhibitors (GDIs) play a primary role in modulating the activation of GTPases by inhibiting the exchange of GDP for GTP. See ARHGDIB (MIM 602843).[supplied by OMIM, Nov 2010]

ARHGDIG links:

ENSG00000286901 (HGNC:):

ENSG00000286901 links:

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ACMG classification

Classification made for transcript

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=0.07102764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIG	NM_001176.4 link	c.245C>T	p.Pro82Leu	missense_variant	Exon 2 of 6	ENST00000219409.8	NP_001167.2	Q99819F1T0H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGDIG	ENST00000219409.8 link	c.245C>T	p.Pro82Leu	missense_variant	Exon 2 of 6	1	NM_001176.4	ENSP00000219409.3		Q99819

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000212

AC:

AN:

235634

Hom.:

AF XY:

0.0000307

AC XY:

AN XY:

130346

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000375

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1434692

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

713252

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000260

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000100

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000168

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245C>T (p.P82L) alteration is located in exon 2 (coding exon 2) of the ARHGDIG gene. This alteration results from a C to T substitution at nucleotide position 245, causing the proline (P) at amino acid position 82 to be replaced by a leucine (L). 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

0.081

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

.;.;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.25

.;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.071

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.80

.;.;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.87

N;N;N

REVEL

Benign

0.0060

Sift

Benign

0.054

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.15

.;.;B

Vest4

0.21

MutPred

0.30

.;Loss of catalytic residue at P81 (P = 0.0151);Loss of catalytic residue at P81 (P = 0.0151);

MVP

0.16

MPC

0.059

ClinPred

0.096

GERP RS

0.38

Varity_R

0.064

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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