X-154439076-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001493.3(GDI1):c.324C>T(p.Ser108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,206,295 control chromosomes in the GnomAD database, including 50 homozygotes. There are 720 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (5 hom., 73 hem., cov: 23)
  • Exomes 𝑓: 0.0022 (45 hom. 647 hem.)
• Consequence: GDI1 NM_001493.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.77

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant X-154439076-C-T is Benign according to our data. Variant chrX-154439076-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.77 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDI1	NM_001493.3	c.324C>T	p.Ser108=	synonymous_variant	4/11	ENST00000447750.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDI1	ENST00000447750.7	c.324C>T	p.Ser108=	synonymous_variant	4/11	1	NM_001493.3	P1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 246 AN: 111262 Hom.: 5 Cov.: 23 AF XY: 0.00218 AC XY: 73 AN XY: 33554

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000496

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000454

Gnomad OTH AF: 0.00401

GnomAD3 exomes AF: 0.00930 AC: 1702 AN: 183064 Hom.: 40 AF XY: 0.00648 AC XY: 438 AN XY: 67598

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.0592

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.000375

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00222 AC: 2430 AN: 1094977 Hom.: 45 Cov.: 30 AF XY: 0.00179 AC XY: 647 AN XY: 360515

Gnomad4 AFR exome AF: 0.000228

Gnomad4 AMR exome AF: 0.0540

Gnomad4 ASJ exome AF: 0.000310

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000444

Gnomad4 FIN exome AF: 0.000446

Gnomad4 NFE exome AF: 0.000478

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00221 AC: 246 AN: 111318 Hom.: 5 Cov.: 23 AF XY: 0.00217 AC XY: 73 AN XY: 33620

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000496

Gnomad4 NFE AF: 0.000454

Gnomad4 OTH AF: 0.00396

Alfa AF: 0.00170 Hom.: 12

Bravo AF: 0.00494

EpiCase AF: 0.000273

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2015	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2014

This alteration is classified as likely 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. -

Intellectual disability, X-linked 41 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 07, 2021

- -

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	-0.28
Cadd	Benign	14
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230286; hg19: chrX-153667422;