16-282070-C-T

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

1
4
14

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]

Genome browser will be placed here

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
ARHGDIGNM_001176.4 linkc.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
ARHGDIGENST00000219409.8 linkc.299C>T p.Ser100Leu missense_variant Exon 3 of 6 1 NM_001176.4 ENSP00000219409.3 Q99819

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152070
Hom.:
0
Cov.:
32
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:
2
AN:
250668
Hom.:
0
AF XY:
0.00
AC XY:
0
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:
15
AN:
1460650
Hom.:
0
Cov.:
36
AF XY:
0.00000826
AC XY:
6
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:
5
AN:
152070
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
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.:
0
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
T
BayesDel_noAF
Benign
-0.26
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
.;.;.;T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.93
.;.;D;D
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.28
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
.;.;.;L
PrimateAI
Uncertain
0.64
T
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
D
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.

Other links and lift over

dbSNP: rs964452083; hg19: chr16-332070; API