X-154532269-C-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong BS2_Supporting

The NM_001360016.2(G6PD):​c.1376G>C​(p.Arg459Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000661 in 1,209,746 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). 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 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 4 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.69
• Publications: 188 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.

• 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 anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant X-154532269-C-G is Pathogenic according to our data. Variant chrX-154532269-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 10422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 4 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>C	p.Arg459Pro	missense	Exon 12 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.1466G>C	p.Arg489Pro	missense	Exon 12 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.1376G>C	p.Arg459Pro	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>C	p.Arg459Pro	missense	Exon 12 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.1376G>C	p.Arg459Pro	missense	Exon 12 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.1514G>C	p.Arg505Pro	missense	Exon 12 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 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: 0.000279

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181938 AF XY: 0.00

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: 0.0000123

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097709 Hom.: 0 Cov.: 37 AF XY: 0.0000110 AC XY: 4 AN XY: 363135

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

American (AMR) AF: 0.00 AC: 0 AN: 35184

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

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

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

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4128

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841892

Other (OTH) AF: 0.0000434 AC: 2 AN: 46077

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 112037 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34197

African (AFR) AF: 0.00 AC: 0 AN: 30888

American (AMR) AF: 0.00 AC: 0 AN: 10623

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

East Asian (EAS) AF: 0.000279 AC: 1 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2716

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53020

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (4)
1	-	-	G6PD deficiency (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	not provided (1)
-	-	-	G6PD COSENZA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.84
Sift	Benign	0.080	T
Sift4G	Benign	0.097	T
Polyphen		0.98	D
Vest4		0.86
MutPred		0.89		Loss of helix (P = 0.1706)
MVP		1.0
MPC		2.4
ClinPred		0.69	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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;