rs137852339

Variant names:

• chrX-154533044-C-T
• rs137852339
• NM_001360016.2:c.949G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 15P and 2B. PS3 PM1 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_001360016.2(G6PD):​c.949G>A​(p.Glu317Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000563 in 1,211,171 control chromosomes in the GnomAD database, including 7 homozygotes. There are 376 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002599307: Decreased activity in red blood cells of hemizygotes (19-52%) (PS3).".

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 20 hem., cov: 24)
  • Exomes 𝑓: 0.00059 (7 hom. 356 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:3
• Conservation: PhyloP100: 2.83
• Publications: 30 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.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002599307: Decreased activity in red blood cells of hemizygotes (19-52%) (PS3).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001360016.2
• 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 class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency, anemia, nonspherocytic hemolytic, due to G6PD deficiency.
• PP5: Variant X-154533044-C-T is Pathogenic according to our data. Variant chrX-154533044-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013208687). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd4 at 20 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	NM_001360016.2	MANE Select	c.949G>A	p.Glu317Lys	missense	Exon 9 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.1039G>A	p.Glu347Lys	missense	Exon 9 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.949G>A	p.Glu317Lys	missense	Exon 9 of 13	NP_001035810.1	P11413-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.949G>A	p.Glu317Lys	missense	Exon 9 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.949G>A	p.Glu317Lys	missense	Exon 9 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.1087G>A	p.Glu363Lys	missense	Exon 9 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.000257 AC: 29 AN: 113000 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00909

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00124 AC: 227 AN: 183230 AF XY: 0.00195

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000595 AC: 653 AN: 1098117 Hom.: 7 Cov.: 33 AF XY: 0.000979 AC XY: 356 AN XY: 363511

African (AFR) AF: 0.00 AC: 0 AN: 26400

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0111 AC: 601 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40451

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4136

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 842091

Other (OTH) AF: 0.000781 AC: 36 AN: 46096

GnomAD4 genome AF: 0.000257 AC: 29 AN: 113054 Hom.: 0 Cov.: 24 AF XY: 0.000568 AC XY: 20 AN XY: 35206

African (AFR) AF: 0.00 AC: 0 AN: 31209

American (AMR) AF: 0.00 AC: 0 AN: 10835

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.00911 AC: 25 AN: 2744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6357

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53259

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.000134 Hom.: 1

Bravo AF: 0.0000982

ExAC AF: 0.00166 AC: 202

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (12)
4	-	-	not provided (4)
2	-	-	G6PD deficiency (2)
1	-	-	Congenital nonspherocytic hemolytic anemia (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)
-	-	-	G6PD KALYAN (1)
-	-	-	G6PD KERALA (1)
-	-	-	G6PD KERALA-KALYAN (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.013	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L
PhyloP100		2.8
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.32	T
Polyphen		0.84	P
Vest4		0.51
MutPred		0.84		Gain of ubiquitination at E317 (P = 0.0048)
MVP		1.0
MPC		1.2
ClinPred		0.073	T
GERP RS		5.5
Varity_R		0.77
gMVP		0.89
Mutation Taster		=63/37	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: rs137852339; hg19: chrX-153761259; COSMIC: COSV104423998; COSMIC: COSV104423998;