rs113696246

Variant names:

• chrX-154438762-C-T
• rs113696246
• NM_001493.3:c.154-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 41

  Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001493.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDI1	NM_001493.3	MANE Select	c.154-3C>T		splice_region intron	N/A	NP_001484.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDI1	ENST00000447750.7	TSL:1 MANE Select	c.154-3C>T		splice_region intron	N/A	ENSP00000394071.2
	GDI1	ENST00000481304.5	TSL:1	n.220-3C>T		splice_region intron	N/A
	GDI1	ENST00000905223.1		c.154-3C>T		splice_region intron	N/A	ENSP00000575282.1

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 594 AN: 112355 Hom.: 3 Cov.: 23

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

GnomAD2 exomes AF: 0.00484 AC: 887 AN: 183443 AF XY: 0.00524

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 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

African (AFR) AF: 0.000735 AC: 19 AN: 25862

American (AMR) AF: 0.00333 AC: 117 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 239 AN: 19229

East Asian (EAS) AF: 0.00 AC: 0 AN: 30104

South Asian (SAS) AF: 0.000953 AC: 51 AN: 53512

European-Finnish (FIN) AF: 0.00121 AC: 49 AN: 40481

Middle Eastern (MID) AF: 0.00981 AC: 40 AN: 4078

European-Non Finnish (NFE) AF: 0.00751 AC: 6143 AN: 817766

Other (OTH) AF: 0.00756 AC: 342 AN: 45224

GnomAD4 genome AF: 0.00528 AC: 593 AN: 112410 Hom.: 3 Cov.: 23 AF XY: 0.00480 AC XY: 166 AN XY: 34574

African (AFR) AF: 0.00107 AC: 33 AN: 30978

American (AMR) AF: 0.00972 AC: 104 AN: 10695

Ashkenazi Jewish (ASJ) AF: 0.00943 AC: 25 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3590

South Asian (SAS) AF: 0.000365 AC: 1 AN: 2741

European-Finnish (FIN) AF: 0.000809 AC: 5 AN: 6182

Middle Eastern (MID) AF: 0.0185 AC: 4 AN: 216

European-Non Finnish (NFE) AF: 0.00754 AC: 401 AN: 53156

Other (OTH) AF: 0.0132 AC: 20 AN: 1520

Alfa AF: 0.00710 Hom.: 61

Bravo AF: 0.00652

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	GDI1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		1.3
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs113696246; hg19: chrX-153667108;