NM_001360016.2:c.844G>C

Variant names:

• chrX-154533596-C-G
• rs137852318
• NM_001360016.2:c.844G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1 PM5 PP2 PP5_Very_Strong BS2_Supporting

The NM_001360016.2(G6PD):​c.844G>C​(p.Asp282His) variant causes a missense change. The variant allele was found at a frequency of 0.000892 in 1,211,000 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 313 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D282Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., 17 hem., cov: 24)
  • Exomes 𝑓: 0.00091 (0 hom. 296 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:2
• Conservation: PhyloP100: 4.62
• Publications: 42 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 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001360016.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154533596-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1722591.Status of the report is criteria_provided_single_submitter, 1 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.
• PP5: Variant X-154533596-C-G is Pathogenic according to our data. Variant chrX-154533596-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 17 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.844G>C	p.Asp282His	missense	Exon 8 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.934G>C	p.Asp312His	missense	Exon 8 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.844G>C	p.Asp282His	missense	Exon 8 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.844G>C	p.Asp282His	missense	Exon 8 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.844G>C	p.Asp282His	missense	Exon 8 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.982G>C	p.Asp328His	missense	Exon 8 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.000718 AC: 81 AN: 112741 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000840

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000361

Gnomad FIN AF: 0.000794

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000655

GnomAD2 exomes AF: 0.000704 AC: 129 AN: 183239 AF XY: 0.000738

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000875

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000910 AC: 999 AN: 1098206 Hom.: 0 Cov.: 32 AF XY: 0.000814 AC XY: 296 AN XY: 363574

African (AFR) AF: 0.0000758 AC: 2 AN: 26402

American (AMR) AF: 0.000511 AC: 18 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.000480 AC: 26 AN: 54146

European-Finnish (FIN) AF: 0.000740 AC: 30 AN: 40524

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4133

European-Non Finnish (NFE) AF: 0.00103 AC: 867 AN: 842116

Other (OTH) AF: 0.00115 AC: 53 AN: 46093

GnomAD4 genome AF: 0.000718 AC: 81 AN: 112794 Hom.: 0 Cov.: 24 AF XY: 0.000487 AC XY: 17 AN XY: 34942

African (AFR) AF: 0.0000964 AC: 3 AN: 31124

American (AMR) AF: 0.000839 AC: 9 AN: 10727

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.000362 AC: 1 AN: 2764

European-Finnish (FIN) AF: 0.000794 AC: 5 AN: 6295

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

European-Non Finnish (NFE) AF: 0.00117 AC: 62 AN: 53213

Other (OTH) AF: 0.000647 AC: 1 AN: 1546

Alfa AF: 0.000903 Hom.: 20

Bravo AF: 0.000737

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.00224

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (10)
7	-	-	not provided (7)
1	-	-	G6PD deficiency (1)
1	-	-	G6PD-related disorder (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)
-	-	-	G6PD MODENA (1)
-	-	-	G6PD SEATTLE-LIKE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.69
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.74
MVP		1.0
MPC		2.2
ClinPred		0.15	T
GERP RS		5.7
Varity_R		0.92
gMVP		0.97
Mutation Taster		=11/89	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: rs137852318; hg19: chrX-153761811;