X-154438762-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001493.3(GDI1):c.154-3C>T variant causes a splice region, 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
NM_001493.3 splice_region, 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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00528 (593/112410) while in subpopulation AMR AF= 0.00972 (104/10695). AF 95% confidence interval is 0.00821. There are 3 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDI1	NM_001493.3 link	c.154-3C>T		splice_region_variant, intron_variant	Intron 2 of 10	ENST00000447750.7	NP_001484.1	P31150A0A0S2Z3X8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDI1	ENST00000447750.7 link	c.154-3C>T		splice_region_variant, intron_variant	Intron 2 of 10	1	NM_001493.3	ENSP00000394071.2		P31150

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

Aug 16, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases

Benign:1

Feb 09, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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