Genetic Variant ARHGDIG:p.Ser100Leu (chr16-282070-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

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

The NM_001176.4(ARHGDIG):c.299C>T(p.Ser100Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,612,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

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: 4.08

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28330773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGDIG	NM_001176.4 link	c.299C>T	p.Ser100Leu	missense_variant	Exon 3 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.299C>T	p.Ser100Leu	missense_variant	Exon 3 of 6	1	NM_001176.4	ENSP00000219409.3		Q99819

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250668

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1460650

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726640

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000387

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.299C>T (p.S100L) alteration is located in exon 3 (coding exon 3) of the ARHGDIG gene. This alteration results from a C to T substitution at nucleotide position 299, causing the serine (S) at amino acid position 100 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

0.21

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;.;.;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.93

.;.;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;.;.;L

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.8

D;N;N;N

REVEL

Benign

0.16

Sift

Benign

0.067

.;T;T;T

Sift4G

Benign

0.070

.;T;D;T

Polyphen

0.64

.;.;.;P

Vest4

0.50

MutPred

0.54

.;.;Loss of disorder (P = 0.0514);Loss of disorder (P = 0.0514);

MVP

0.51

MPC

0.055

ClinPred

0.60

GERP RS

3.0

Varity_R

0.080

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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