X-154532434-C-G

Position:

• chrX-154532434-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001360016.2(G6PD):​c.1316G>C​(p.Arg439Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 25)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2 O:1
• Conservation: PhyloP100: 5.66

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant X-154532434-C-G is Pathogenic according to our data. Variant chrX-154532434-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10399.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=3}. Variant chrX-154532434-C-G is described in Lovd as [Pathogenic]. Variant chrX-154532434-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1316G>C	p.Arg439Pro	missense_variant	11/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1406G>C	p.Arg469Pro	missense_variant	11/13		NP_000393.4
G6PD	NM_001042351.3	c.1316G>C	p.Arg439Pro	missense_variant	11/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1316G>C	p.Arg439Pro	missense_variant	11/13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 25

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:3 Uncertain:1

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 (7%) (PS3). Not found in gnomAD (PM2). Reported as pathogenic by clinical testing group (PP5). Post_P 0.975 (odds of pathogenicity 350.3, Prior_P 0.1). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 11, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 30, 2022	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 439 of the G6PD protein (p.Arg439Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of G6PD defiency (PMID: 1611091). This variant is also known as the Pawnee variant. ClinVar contains an entry for this variant (Variation ID: 10399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2022	- -

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2023	Identified in individuals with features of G6PD deficiency and described as the Pawnee variant (PMID: 1611091); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30206300, 2190319, 22293322, 1611091) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 23, 2017	- -

G6PD PAWNEE Other:1

other, no assertion criteria provided

literature only

OMIM

Oct 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.4	H;H;H;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.1	.;.;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0070	.;.;D;D
Sift4G	Uncertain	0.0080	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.96
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		1.0
gMVP		1.0

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: rs137852337; hg19: chrX-153760649;