X-154438830-T-C

Position:

• chrX-154438830-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000447750.7(GDI1):​c.219T>C​(p.Asn73=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,203,854 control chromosomes in the GnomAD database, including 16,368 homozygotes. There are 63,336 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5016 hom., 8578 hem., cov: 23)
  • Exomes 𝑓: 0.15 (11352 hom. 54758 hem.)
• Consequence: GDI1 ENST00000447750.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.21

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-154438830-T-C is Benign according to our data. Variant chrX-154438830-T-C is described in ClinVar as [Benign]. Clinvar id is 129149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154438830-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDI1	NM_001493.3	c.219T>C	p.Asn73=	synonymous_variant	3/11	ENST00000447750.7	NP_001484.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDI1	ENST00000447750.7	c.219T>C	p.Asn73=	synonymous_variant	3/11	1	NM_001493.3	ENSP00000394071	P1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 30214 AN: 109853 Hom.: 5001 Cov.: 23 AF XY: 0.264 AC XY: 8538 AN XY: 32385

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.0867

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.0943

Gnomad EAS AF: 0.0711

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.257

GnomAD3 exomes AF: 0.180 AC: 32984 AN: 183494 Hom.: 3232 AF XY: 0.170 AC XY: 11558 AN XY: 67930

Gnomad AFR exome AF: 0.637

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.0981

Gnomad EAS exome AF: 0.0521

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.152 AC: 166163 AN: 1093942 Hom.: 11352 Cov.: 29 AF XY: 0.152 AC XY: 54758 AN XY: 359750

Gnomad4 AFR exome AF: 0.647

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0738

Gnomad4 SAS exome AF: 0.222

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.275 AC: 30278 AN: 109912 Hom.: 5016 Cov.: 23 AF XY: 0.264 AC XY: 8578 AN XY: 32452

Gnomad4 AFR AF: 0.621

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.0943

Gnomad4 EAS AF: 0.0702

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.267

Alfa AF: 0.179 Hom.: 3535

Bravo AF: 0.294

EpiCase AF: 0.127

EpiControl AF: 0.125

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2015

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. -

Intellectual disability, X-linked 41 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.7
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs4834; hg19: chrX-153667176; COSMIC: COSV63895221; COSMIC: COSV63895221;