rs199586268

Positions:

• chrX-154532470-GGA-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6 BS1 BS2_Supporting

The ENST00000393562.10(G6PD):​c.1288-10_1288-9del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,209,692 control chromosomes in the GnomAD database, including 23 homozygotes. There are 514 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0085 (13 hom., 261 hem., cov: 24)
  • Exomes 𝑓: 0.00090 (10 hom. 253 hem.)
• Consequence: G6PD ENST00000393562.10 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.707

Genes affected

G6PD (HGNC:4057): (glucose-6-phosphate dehydrogenase) This gene encodes glucose-6-phosphate dehydrogenase. This protein is a cytosolic enzyme encoded by a housekeeping X-linked gene whose main function is to produce NADPH, a key electron donor in the defense against oxidizing agents and in reductive biosynthetic reactions. G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. G6PD deficiency may cause neonatal jaundice, acute hemolysis, or severe chronic non-spherocytic hemolytic anemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant X-154532470-GGA-G is Benign according to our data. Variant chrX-154532470-GGA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193829.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0085 (957/112639) while in subpopulation AFR AF= 0.0286 (888/31063). AF 95% confidence interval is 0.027. There are 13 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 XL geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1288-10_1288-9del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1378-10_1378-9del		splice_polypyrimidine_tract_variant, intron_variant			NP_000393.4
G6PD	NM_001042351.3	c.1288-10_1288-9del		splice_polypyrimidine_tract_variant, intron_variant			NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1288-10_1288-9del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001360016.2	ENSP00000377192	P4

Frequencies

GnomAD3 genomes AF: 0.00848 AC: 955 AN: 112589 Hom.: 13 Cov.: 24 AF XY: 0.00751 AC XY: 261 AN XY: 34739

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00457

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000362

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00237 AC: 432 AN: 182556 Hom.: 4 AF XY: 0.00162 AC XY: 109 AN XY: 67266

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000986

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000896 AC: 983 AN: 1097053 Hom.: 10 AF XY: 0.000698 AC XY: 253 AN XY: 362519

Gnomad4 AFR exome AF: 0.0292

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000725

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00850 AC: 957 AN: 112639 Hom.: 13 Cov.: 24 AF XY: 0.00750 AC XY: 261 AN XY: 34799

Gnomad4 AFR AF: 0.0286

Gnomad4 AMR AF: 0.00456

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000363

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000940

Gnomad4 OTH AF: 0.00849

Alfa AF: 0.00421 Hom.: 20

Bravo AF: 0.00972

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 27, 2018	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 21, 2021

- -

G6PD deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

G6PD-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs199586268; hg19: chrX-153760685;