rs137852349

Positions:

• chrX-154535996-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001360016.2(G6PD):​c.208T>C​(p.Tyr70His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,098,064 control chromosomes in the GnomAD database, including 1 homozygotes. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y70C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (1 hom. 3 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 8.73

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360016.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154535995-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant X-154535996-A-G is Pathogenic according to our data. Variant chrX-154535996-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154535996-A-G is described in Lovd as [Pathogenic]. Variant chrX-154535996-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.208T>C	p.Tyr70His	missense_variant	4/13	ENST00000393562.10
G6PD	NM_000402.4	c.298T>C	p.Tyr100His	missense_variant	4/13
G6PD	NM_001042351.3	c.208T>C	p.Tyr70His	missense_variant	4/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.208T>C	p.Tyr70His	missense_variant	4/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000218 AC: 4 AN: 183344 Hom.: 1 AF XY: 0.0000147 AC XY: 1 AN XY: 67828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098064 Hom.: 1 Cov.: 31 AF XY: 0.00000825 AC XY: 3 AN XY: 363428

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: 0.0000739

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	This variant in exon 4 of the G6PD gene results in the amino acid substitution from Tyrosine to Histidine at codon 100 (p.Tyr100His) with the sequence change of c.298T>C (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at Lifecell diagnostics. There is a moderate physicochemical difference between Tyrosine and Histidine. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This variant lies in the Glucose-6-phosphate dehydrogenase, NAD binding domain of the Glucose-6-phosphate 1-dehydrogenase protein (http://pfam.xfam.org/family/G6PD_N). This is a Class II variant associated with moderate G6PD deficiency (<10% activity), with intermittent hemolysis. This variant is also known as G6PD Namoru in the literature. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by Arunachalam AK et al., 2019 and Chalvam R., et al. 2007; PMID: 17233850, Ganczakowski M et al. 1995; PMID: 7825590. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 10, 2022	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 70 of the G6PD protein (p.Tyr70His). This variant is present in population databases (rs137852349, gnomAD 0.02%). This missense change has been observed in individual(s) with G6PD-related conditions (PMID: 7825590, 17233850, 33069889). ClinVar contains an entry for this variant (Variation ID: 10416). 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. This variant disrupts the p.Tyr70 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7577654, 20621077, 21446359; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency and anemia (PS4_M, PP4). Decreased activity in red blood cells (4-33%) (PS3). Predicted to be damaging by SIFT and PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 04, 2022	- -

G6PD NAMORU 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
Sift4G	Pathogenic	0.0	D;.;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.58
MutPred		0.92		Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);Gain of methylation at R72 (P = 0.098);
MVP		1.0
MPC		0.77
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.94

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: rs137852349; hg19: chrX-153764211;