rs137852337

Variant names:

• chrX-154532434-C-G
• rs137852337
• NM_001360016.2:c.1316G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-154532434-C-G
• chrX-154532434-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R439H) has been classified as Uncertain significance.

• 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
• Publications: 12 publications found

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]

G6PD Gene-Disease associations (from GenCC):

• anemia, nonspherocytic hemolytic, due to G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• G6PD deficiency

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• class I glucose-6-phosphate dehydrogenase deficiency

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532435-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1206418.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 185 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. Gene score misZ: 2.0008 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.
• 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 VariationId is 10399.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1316G>C	p.Arg439Pro	missense_variant	Exon 11 of 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

Aug 12, 2022

Dunham Lab, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Sep 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 11, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 23, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:1

Nov 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 23, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

G6PD PAWNEE Other:1

Oct 11, 2024

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;.
PhyloP100		5.7
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
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs137852337; hg19: chrX-153760649;