rs78478128

Variant names:

• chrX-154536168-G-C
• rs78478128
• NM_001360016.2:c.131C>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PS3 PM1 PM5 PP2 PP5_Very_Strong BS2_Supporting

The NM_001360016.2(G6PD):​c.131C>G​(p.Ala44Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,209,580 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000828676: Experimental studies have shown that this missense change affects G6PD function (PMID:8533762)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A44T) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 65 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 6.38
• Publications: 44 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000828676: Experimental studies have shown that this missense change affects G6PD function (PMID: 8533762).; SCV001443094: Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995; PMID:8533762).; SCV002599317: Decreased activity in red blood cells (5-33%) (PS3).; SCV004046941: Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995).; SCV001756317: Functional analysis of recombinant enzyme showed significantly increased Km-NADP and increased thermostability (Kaeda et al., 1995); SCV005878356: Functional analyses of the variant protein show reduced G6PD enzymatic activity (Kaeda 1995). PMID: 8533762; SCV004014691: Functional studies of purified enzyme have demonstrated that this variant causes an increase in Km for NADP+, which results in a reduced G6PD enzyme activity level (PMID: 8533762).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001360016.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154536169-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1722650.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-154536168-G-C is Pathogenic according to our data. Variant chrX-154536168-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 8 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.131C>G	p.Ala44Gly	missense	Exon 3 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.221C>G	p.Ala74Gly	missense	Exon 3 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.131C>G	p.Ala44Gly	missense	Exon 3 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.131C>G	p.Ala44Gly	missense	Exon 3 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.131C>G	p.Ala44Gly	missense	Exon 3 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.131C>G	p.Ala44Gly	missense	Exon 3 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 111652 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: 0.00

Gnomad SAS AF: 0.00492

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 31 AN: 183304 AF XY: 0.000295

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 121 AN: 1097872 Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 65 AN XY: 363234

African (AFR) AF: 0.0000379 AC: 1 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

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

South Asian (SAS) AF: 0.00187 AC: 101 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841799

Other (OTH) AF: 0.000412 AC: 19 AN: 46079

GnomAD4 genome AF: 0.000116 AC: 13 AN: 111708 Hom.: 0 Cov.: 23 AF XY: 0.000236 AC XY: 8 AN XY: 33886

African (AFR) AF: 0.00 AC: 0 AN: 30754

American (AMR) AF: 0.00 AC: 0 AN: 10576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3544

South Asian (SAS) AF: 0.00493 AC: 13 AN: 2637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6127

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53000

Other (OTH) AF: 0.00 AC: 0 AN: 1538

Alfa AF: 0.0000126 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000272 AC: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (7)
4	-	-	not provided (4)
1	-	-	G6PD deficiency (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)
-	-	-	G6PD ORISSA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.77
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		6.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.95		Gain of disorder (P = 0.0537)
MVP		1.0
MPC		0.71
ClinPred		0.45	T
GERP RS		5.4
Varity_R		0.98
gMVP		0.94
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		0.0
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: rs78478128; hg19: chrX-153764383;