NM_001360016.2:c.466G>A

Variant names:

• chrX-154535187-C-T
• rs137852313
• NM_001360016.2:c.466G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 7P and 5B. PS3 PM1 PP2 BP4_Strong BS2_Supporting

The NM_001360016.2(G6PD):​c.466G>A​(p.Glu156Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000868 in 1,209,283 control chromosomes in the GnomAD database, including 2 homozygotes. There are 34 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002599191: Decreased activity in red blood cells of hemizygotes (21-25%) (PS3).".

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000081 (2 hom. 29 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:1 O:1
• Conservation: PhyloP100: 0.964
• Publications: 15 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: Uncertain_significance. The variant received 2 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002599191: Decreased activity in red blood cells of hemizygotes (21-25%) (PS3).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.060296565).
• BS2: High Hemizygotes in GnomAd4 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_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.466G>A	p.Glu156Lys	missense	Exon 5 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.556G>A	p.Glu186Lys	missense	Exon 5 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.466G>A	p.Glu156Lys	missense	Exon 5 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.466G>A	p.Glu156Lys	missense	Exon 5 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.466G>A	p.Glu156Lys	missense	Exon 5 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.466G>A	p.Glu156Lys	missense	Exon 5 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.000143 AC: 16 AN: 111791 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.000666

GnomAD2 exomes AF: 0.000273 AC: 50 AN: 183269 AF XY: 0.000266

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000811 AC: 89 AN: 1097438 Hom.: 2 Cov.: 31 AF XY: 0.0000799 AC XY: 29 AN XY: 363082

African (AFR) AF: 0.000607 AC: 16 AN: 26379

American (AMR) AF: 0.000966 AC: 34 AN: 35207

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

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

South Asian (SAS) AF: 0.000444 AC: 24 AN: 54113

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.000550 AC: 2 AN: 3635

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841957

Other (OTH) AF: 0.0000652 AC: 3 AN: 46033

GnomAD4 genome AF: 0.000143 AC: 16 AN: 111845 Hom.: 0 Cov.: 23 AF XY: 0.000147 AC XY: 5 AN XY: 34049

African (AFR) AF: 0.000389 AC: 12 AN: 30827

American (AMR) AF: 0.000188 AC: 2 AN: 10645

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52974

Other (OTH) AF: 0.000658 AC: 1 AN: 1520

Alfa AF: 0.0000848 Hom.: 2

Bravo AF: 0.000276

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000313 AC: 38

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	1	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (4)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	-	-	G6PD ILESHA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	16
DANN	Benign	0.67
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Benign	0.027	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.060	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.49	N
PhyloP100		0.96
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.55
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.20
MVP		0.99
MPC		0.20
ClinPred		0.0018	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.56
Mutation Taster		=76/24	polymorphism

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: rs137852313; hg19: chrX-153763402;