rs1557230573

Variant names:

• chrX-154535205-C-T
• rs1557230573
• NM_001360016.2:c.448G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_001360016.2(G6PD):​c.448G>A​(p.Val150Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,759 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.51
• Publications: 2 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 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant X-154535205-C-T is Pathogenic according to our data. Variant chrX-154535205-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 544826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.448G>A	p.Val150Ile	missense_variant	Exon 5 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.538G>A	p.Val180Ile	missense_variant	Exon 5 of 13		NP_000393.4
G6PD	NM_001042351.3	c.448G>A	p.Val150Ile	missense_variant	Exon 5 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.448G>A	p.Val150Ile	missense_variant	Exon 5 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097759 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363255

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000379 AC: 1 AN: 26390

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3844

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 842026

Other (OTH) AF: 0.00 AC: 0 AN: 46052

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 150 of the G6PD protein (p.Val150Ile). 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 and/or hemolytic anemia (PMID: 32641076, 33128437). This variant is also known as p.V180I, G6PD Baise. ClinVar contains an entry for this variant (Variation ID: 544826). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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 of hemizygote (4%) (PS3). Not observed in gnomAD (PM2). Post_P 0.949 (odds of pathogenicity 168.4, Prior_P 0.1). -

Familial hemolytic anemia Pathogenic:1

Feb 27, 2018

Department of Genetic, Henri Mondor Hospital, Assistance Publique des Hôpitaux de Paris

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malaria, susceptibility to Pathogenic:1

Jan 30, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	.;.;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.2	L;L;L;L;.;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.85	.;.;N;N;N;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.044	.;.;D;D;D;D;D
Sift4G	Uncertain	0.049	D;.;D;T;.;.;.
Polyphen		0.97	D;D;D;.;.;.;.
Vest4		0.24
MutPred		0.55		Gain of methylation at K152 (P = 0.0767);Gain of methylation at K152 (P = 0.0767);Gain of methylation at K152 (P = 0.0767);Gain of methylation at K152 (P = 0.0767);Gain of methylation at K152 (P = 0.0767);Gain of methylation at K152 (P = 0.0767);Gain of methylation at K152 (P = 0.0767);
MVP		0.91
MPC		0.64
ClinPred		0.77	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.62
Mutation Taster		=53/47	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1557230573; hg19: chrX-153763420; COSMIC: COSV63705075; COSMIC: COSV63705075;