X-154438762-C-T

Position:

chrX-154438762-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The ENST00000447750.7(GDI1):c.154-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00641 in 1,183,841 control chromosomes in the GnomAD database, including 26 homozygotes. There are 2,310 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 3 hom., 166 hem., cov: 23)

Exomes 𝑓: 0.0065 ( 23 hom. 2144 hem. )

Consequence

GDI1
ENST00000447750.7 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.001483

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.25

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]

GDI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant X-154438762-C-T is Benign according to our data. Variant chrX-154438762-C-T is described in ClinVar as [Benign]. Clinvar id is 129148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154438762-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDI1	NM_001493.3 linkuse as main transcript	c.154-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000447750.7	NP_001484.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDI1	ENST00000447750.7 linkuse as main transcript	c.154-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001493.3	ENSP00000394071	P1

Frequencies

GnomAD3 genomes

AF:

0.00529

AC:

594

AN:

112355

Hom.:

Cov.:

AF XY:

0.00481

AC XY:

166

AN XY:

34509

show subpopulations

Gnomad AFR

AF:

0.00107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00974

Gnomad ASJ

AF:

0.00943

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000364

Gnomad FIN

AF:

0.000809

Gnomad MID

AF:

0.0211

Gnomad NFE

AF:

0.00754

Gnomad OTH

AF:

0.0133

GnomAD3 exomes

AF:

0.00484

AC:

887

AN:

183443

Hom.:

AF XY:

0.00524

AC XY:

356

AN XY:

67881

show subpopulations

Gnomad AFR exome

AF:

0.000532

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000839

Gnomad FIN exome

AF:

0.000751

Gnomad NFE exome

AF:

0.00837

Gnomad OTH exome

AF:

0.00485

GnomAD4 exome

AF:

0.00653

AC:

7000

AN:

1071431

Hom.:

Cov.:

AF XY:

0.00629

AC XY:

2144

AN XY:

340975

show subpopulations

Gnomad4 AFR exome

AF:

0.000735

Gnomad4 AMR exome

AF:

0.00333

Gnomad4 ASJ exome

AF:

0.0124

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000953

Gnomad4 FIN exome

AF:

0.00121

Gnomad4 NFE exome

AF:

0.00751

Gnomad4 OTH exome

AF:

0.00756

GnomAD4 genome

AF:

0.00528

AC:

593

AN:

112410

Hom.:

Cov.:

AF XY:

0.00480

AC XY:

166

AN XY:

34574

show subpopulations

Gnomad4 AFR

AF:

0.00107

Gnomad4 AMR

AF:

0.00972

Gnomad4 ASJ

AF:

0.00943

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000365

Gnomad4 FIN

AF:

0.000809

Gnomad4 NFE

AF:

0.00754

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.00710

Hom.:

Bravo

AF:

0.00652

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

GDI1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0015

dbscSNV1_RF

Benign

0.056

SpliceAI score (max)

0.030

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