rs72554665

Variant names:

• chrX-154532269-C-A
• rs72554665
• NM_001360016.2:c.1376G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-154532269-C-A
• chrX-154532269-C-G
• chrX-154532269-C-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 17P and 2B. PS3 PM1 PM5 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_001360016.2(G6PD):​c.1376G>T​(p.Arg459Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000133 in 1,209,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000768476: Experimental studies have shown that this missense change affects G6PD function (PMID:16607506)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R459G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 12 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 32 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:4
• Conservation: PhyloP100: 3.69
• Publications: 197 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000768476: Experimental studies have shown that this missense change affects G6PD function (PMID: 16607506).; SCV002599395: Decreased activity in red blood cells (1-52%) (PS3).; SCV005416896: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV005908351: Previous experiments have shown that this missense variation will lead to enzyme activity and affinity for glucose 6- phosphate. Significantly decreased (PMID:16607506), the mutation of the same site leading to the change to another amino acid has been confirmed to be pathogenic.; SCV001142504: Experimental studies have shown that this missense change causes a significant reduction in enzyme activity and affinity for glucose-6-phosphate (PMID: 16607506).; SCV003929741: "In vitro functional studies indicate that R459L has a reduced catalytic efficiency of approximately 50% compared to wild type enzyme (Boonyuen et al., 2017);"
• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001360016.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532270-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1722634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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-154532269-C-A is Pathogenic according to our data. Variant chrX-154532269-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 100058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014364898). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd4 at 12 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.1376G>T	p.Arg459Leu	missense	Exon 12 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.1466G>T	p.Arg489Leu	missense	Exon 12 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.1376G>T	p.Arg459Leu	missense	Exon 12 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.1376G>T	p.Arg459Leu	missense	Exon 12 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.1376G>T	p.Arg459Leu	missense	Exon 12 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.1514G>T	p.Arg505Leu	missense	Exon 12 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 28 AN: 112037 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00781

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000813 AC: 148 AN: 181938 AF XY: 0.000584

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 133 AN: 1097708 Hom.: 0 Cov.: 37 AF XY: 0.0000881 AC XY: 32 AN XY: 363134

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.0000284 AC: 1 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00407 AC: 123 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54083

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40371

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841892

Other (OTH) AF: 0.000195 AC: 9 AN: 46077

GnomAD4 genome AF: 0.000250 AC: 28 AN: 112090 Hom.: 0 Cov.: 23 AF XY: 0.000350 AC XY: 12 AN XY: 34260

African (AFR) AF: 0.00 AC: 0 AN: 30957

American (AMR) AF: 0.00 AC: 0 AN: 10636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00784 AC: 28 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53013

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.0000349 Hom.: 0

Bravo AF: 0.000276

ExAC AF: 0.000577 AC: 70

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (9)
4	-	-	not provided (4)
2	-	-	G6PD deficiency (2)
1	-	-	G6PD-related disorder (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)
-	-	-	G6PD AGRIGENTO (1)
-	-	-	G6PD CANTON (1)
-	-	-	G6PD GIFU (1)
-	-	-	G6PD TAIWAN-HAKKA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.59
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.014	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L
PhyloP100		3.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.70
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.73	P
Vest4		0.56
MVP		1.0
MPC		1.9
ClinPred		0.20	T
GERP RS		5.6
Varity_R		0.72
gMVP		0.96
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs72554665; hg19: chrX-153760484;