rs137852315

Variant names:

• chrX-154536032-C-G
• rs137852315
• NM_001360016.2:c.172G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-154536032-C-G
• chrX-154536032-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM5 PP2 PP3_Moderate BS2_Supporting

The NM_001360016.2(G6PD):​c.172G>C​(p.Asp58His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,097,456 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D58N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 2 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 8 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-154536032-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 10369.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• 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). GenCC associations: The gene is linked to class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency, anemia, nonspherocytic hemolytic, due to G6PD deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.172G>C	p.Asp58His	missense_variant	Exon 4 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.262G>C	p.Asp88His	missense_variant	Exon 4 of 13		NP_000393.4
G6PD	NM_001042351.3	c.172G>C	p.Asp58His	missense_variant	Exon 4 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.172G>C	p.Asp58His	missense_variant	Exon 4 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000729 AC: 8 AN: 1097456 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 362818

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26380

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35204

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19386

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30205

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 54124

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40520

Gnomad4 NFE exome AF: 0.00000951 AC: 8 AN: 841432

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 46073

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;D;.;D;.;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M;M;M;M;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.3	.;.;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Benign	0.15	.;.;T;T;T;T;D
Sift4G	Benign	0.20	T;.;T;T;.;.;.
Polyphen		0.98	D;D;D;.;.;.;.
Vest4		0.79
MutPred		0.68		Loss of stability (P = 0.0677);Loss of stability (P = 0.0677);Loss of stability (P = 0.0677);Loss of stability (P = 0.0677);Loss of stability (P = 0.0677);Loss of stability (P = 0.0677);Loss of stability (P = 0.0677);
MVP		0.99
MPC		0.78
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.86
gMVP		0.94
Mutation Taster		=12/88	disease causing

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: rs137852315; hg19: chrX-153764247;