X-154438762-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001493.3(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 NM_001493.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001483
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.25

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]

ACMG classification

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 GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDI1	NM_001493.3	c.154-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000447750.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 594 AN: 112355 Hom.: 3 Cov.: 23 AF XY: 0.00481 AC XY: 166 AN XY: 34509

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.: 1 AF XY: 0.00524 AC XY: 356 AN XY: 67881

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.: 23 Cov.: 27 AF XY: 0.00629 AC XY: 2144 AN XY: 340975

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.: 3 Cov.: 23 AF XY: 0.00480 AC XY: 166 AN XY: 34574

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.: 61

Bravo AF: 0.00652

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

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	- -

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, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	13
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

Other links and lift over

dbSNP: rs113696246; hg19: chrX-153667108;