X-154438580-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The ENST00000447750.7(GDI1):​c.103C>T​(p.Arg35Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,337 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

GDI1
ENST00000447750.7 missense

Scores

12
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83
Variant links:
Genes affected
GDI1 (HGNC:4226): (GDP dissociation inhibitor 1) GDP dissociation inhibitors are proteins that regulate the GDP-GTP exchange reaction of members of the rab family, small GTP-binding proteins of the ras superfamily, that are involved in vesicular trafficking of molecules between cellular organelles. GDIs slow the rate of dissociation of GDP from rab proteins and release GDP from membrane-bound rabs. GDI1 is expressed primarily in neural and sensory tissues. Mutations in GDI1 have been linked to X-linked nonspecific cognitive disability. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GDI1. . Gene score misZ 3.2905 (greater than the threshold 3.09). GenCC has associacion of gene with intellectual disability, X-linked 41, non-syndromic X-linked intellectual disability.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GDI1NM_001493.3 linkuse as main transcriptc.103C>T p.Arg35Trp missense_variant 2/11 ENST00000447750.7 NP_001484.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GDI1ENST00000447750.7 linkuse as main transcriptc.103C>T p.Arg35Trp missense_variant 2/111 NM_001493.3 ENSP00000394071 P1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
9.17e-7
AC:
1
AN:
1090337
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
356111
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000120
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 16, 2020Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
.;D
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Pathogenic
3.4
.;M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-7.0
.;D
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
.;D
Sift4G
Uncertain
0.043
D;D
Polyphen
1.0
.;D
Vest4
0.81
MutPred
0.82
Loss of disorder (P = 0.0207);Loss of disorder (P = 0.0207);
MVP
0.99
MPC
2.4
ClinPred
1.0
D
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.91
gMVP
0.98

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: chrX-153666926; API