X-154532203-G-C

Variant names:

• chrX-154532203-G-C
• rs137852348
• NM_001360016.2:c.1442C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001360016.2(G6PD):​c.1442C>G​(p.Pro481Arg) 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. P481A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 3 hem.)
  • Failed GnomAD Quality Control
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 5.85

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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532203-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3771514.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant X-154532203-G-C is Pathogenic according to our data. Variant chrX-154532203-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10415.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chrX-154532203-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1442C>G	p.Pro481Arg	missense_variant	Exon 12 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1532C>G	p.Pro511Arg	missense_variant	Exon 12 of 13		NP_000393.4
G6PD	NM_001042351.3	c.1442C>G	p.Pro481Arg	missense_variant	Exon 12 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1442C>G	p.Pro481Arg	missense_variant	Exon 12 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000273 AC: 3 AN: 1097907 Hom.: 0 Cov.: 37 AF XY: 0.00000826 AC XY: 3 AN XY: 363335

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1 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 (PP4). Decreased actvity in red blood cells (30%) (PS3). Not found in gnomAD (PM2). Not found in gnomAD (PM2). Post_P 0.949 (odds of pathogenicity 168.4, Prior_P 0.1). -

Aug 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 481 of the G6PD protein (p.Pro481Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 16143877). This variant is also known as G6PD Split. ClinVar contains an entry for this variant (Variation ID: 10415). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. 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. -

G6PD SPLIT Other:1

Jul 28, 2016

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	Benign	0.13
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D;D;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.5	.;.;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.016	.;.;D;D
Sift4G	Benign	0.18	T;.;T;T
Polyphen		0.46	P;P;P;.
Vest4		0.70
MutPred		0.72		Loss of ubiquitination at K476 (P = 0.0391);Loss of ubiquitination at K476 (P = 0.0391);Loss of ubiquitination at K476 (P = 0.0391);.;
MVP		0.99
MPC		1.6
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.57
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137852348; hg19: chrX-153760418;