rs137852338

chrX-154546045-CATG-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM4_Supporting PP5

The NM_001360016.2(G6PD):c.108_110del(p.Ile36del) variant causes a inframe deletion change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: G6PD NM_001360016.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 6.97

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]

IKBKG (HGNC:5961): (inhibitor of nuclear factor kappa B kinase regulatory subunit gamma) This gene encodes the regulatory subunit of the inhibitor of kappaB kinase (IKK) complex, which activates NF-kappaB resulting in activation of genes involved in inflammation, immunity, cell survival, and other pathways. Mutations in this gene result in incontinentia pigmenti, hypohidrotic ectodermal dysplasia, and several other types of immunodeficiencies. A pseudogene highly similar to this locus is located in an adjacent region of the X chromosome. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360016.2
• PM4: Nonframeshift variant in NON repetitive region in NM_001360016.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-154546045-CATG-C is Pathogenic according to our data. Variant chrX-154546045-CATG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10400.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chrX-154546045-CATG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.108_110del	p.Ile36del	inframe_deletion	2/13	ENST00000393562.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.108_110del	p.Ile36del	inframe_deletion	2/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in hemizygote with G6PD deficiency and CNSHA (PP4). Decreased activity in red blood cells of hemizygote (PS3). Leads to deletion of one amino acid (PM4) and is not observed in gnomAD (PM2). Post_P 0.989 (odds of pathogenicity 729.3, Prior_P 0.1). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 14, 1991	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 04, 2020

The G6PD c.108_110delCAT; p.Ile36del variant (rs137852338), also known as G6PD Sunderland or p.Ile66del on NM_000402.4, is reported in the literature in the hemizygous state in an individual affected with G6PD deficiency and chronic hemolytic anemia (MacDonald 1991). This variant deletes a single isoleucine residue leaving the rest of the protein in-frame. This variant is reported in ClinVar (Variation ID: 10400), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. However, given the lack of clinical and functional data, the significance of the p.Ile36del variant is uncertain at this time. References: MacDonald D et al. Deficiency in red blood cells. Nature. 1991;350(6314):115. References: MacDonald D et al. Deficiency in red blood cells. Nature. 1991;350(6314):115. -

G6PD SUNDERLAND Other:1

other, no assertion criteria provided

literature only

OMIM

Oct 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

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: rs137852338; hg19: chrX-153774260;