rs137852344

Positions:

• chrX-154532245-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001360016.2(G6PD):​c.1400C>G​(p.Pro467Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.30

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-154532245-G-C is Pathogenic according to our data. Variant chrX-154532245-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154532245-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1400C>G	p.Pro467Arg	missense_variant	12/13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1490C>G	p.Pro497Arg	missense_variant	12/13		NP_000393.4
G6PD	NM_001042351.3	c.1400C>G	p.Pro467Arg	missense_variant	12/13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1400C>G	p.Pro467Arg	missense_variant	12/13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1098016 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 1 AN XY: 363414

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2023	ClinVar contains an entry for this variant (Variation ID: 10409). 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 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. This missense change has been observed in individuals with glucose-6-phosphate dehydrogenase deficiency (PMID: 9233561, 24134566). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 467 of the G6PD protein (p.Pro467Arg). This variant is not present in population databases (gnomAD no frequency). -
Likely pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in hemizygotes with G6PD deficiency (PP4). Decreased actvity in red blood cells (30-45%) (PS3). Not found in gnomAD (PM2). Not found in gnomAD (PM2). Post_P 0.949 (odds of pathogenicity 168.4, Prior_P 0.1). -

G6PD NEAPOLIS Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.3	M;M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.7	.;.;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.98
MutPred		0.92		Gain of MoRF binding (P = 0.004);Gain of MoRF binding (P = 0.004);Gain of MoRF binding (P = 0.004);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.98

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: rs137852344; hg19: chrX-153760460;