rs76645461

Variant names:

• chrX-154536156-A-G
• rs76645461
• NM_001360016.2:c.143T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PP2 PP3_Moderate PP5_Very_Strong BS2_Supporting

The NM_000402.4(G6PD):​c.233T>C​(p.Ile78Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,209,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 5 hem.)
• Consequence: G6PD NM_000402.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 7.09
• Publications: 36 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 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000402.4
• 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, 0.925
• PP5: Variant X-154536156-A-G is Pathogenic according to our data. Variant chrX-154536156-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 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_000402.4. 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.143T>C	p.Ile48Thr	missense	Exon 3 of 13	NP_001346945.1
	G6PD	NM_000402.4		c.233T>C	p.Ile78Thr	missense	Exon 3 of 13	NP_000393.4
	G6PD	NM_001042351.3		c.143T>C	p.Ile48Thr	missense	Exon 3 of 13	NP_001035810.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.143T>C	p.Ile48Thr	missense	Exon 3 of 13	ENSP00000377192.3
	G6PD	ENST00000696421.1		c.143T>C	p.Ile48Thr	missense	Exon 3 of 13	ENSP00000512616.1
	G6PD	ENST00000369620.6	TSL:5	c.143T>C	p.Ile48Thr	missense	Exon 3 of 13	ENSP00000358633.2

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111765 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: 0.000281

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: 0.0000109 AC: 2 AN: 183351 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1098104 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363460

African (AFR) AF: 0.0000379 AC: 1 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00242 AC: 10 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842009

Other (OTH) AF: 0.0000868 AC: 4 AN: 46088

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111822 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34014

African (AFR) AF: 0.00 AC: 0 AN: 30821

American (AMR) AF: 0.00 AC: 0 AN: 10609

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.000282 AC: 1 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2653

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6105

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53012

Other (OTH) AF: 0.00 AC: 0 AN: 1535

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (8)
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 AURES (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.63
CADD	Uncertain	25
DANN	Benign	0.88
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.4	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.80
Sift	Benign	1.0	T
Sift4G	Benign	0.77	T
Polyphen		0.98	D
Vest4		0.80
MutPred		0.96		Gain of disorder (P = 0.0198)
MVP		1.0
MPC		0.80
ClinPred		0.35	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.98
Mutation Taster		=1/99	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: rs76645461; hg19: chrX-153764371;