rs5030869

Variant names:

• chrX-154532990-C-T
• rs5030869
• NM_001360016.2:c.1003G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-154532990-C-T
• chrX-154532990-C-A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 17P and 2B. PS3 PM1 PM5 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_001360016.2(G6PD):​c.1003G>A​(p.Ala335Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,210,823 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000768477: Experimental studies have shown that this missense change affects G6PD function (PMID:3393536)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A335D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.00013 (0 hom. 78 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:24 U:1 O:1
• Conservation: PhyloP100: 0.969
• Publications: 59 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000768477: Experimental studies have shown that this missense change affects G6PD function (PMID: 3393536).; SCV001443773: Experimental studies have shown that this missense change affects substrate affinity and stability of the glucose-6-phosphate dehydrogenase protein (Vulliamy et al., 1988; PMID:3393536); SCV002599353: Decreased activity in red blood cells (0-32%) (PS3).; SCV004175849: Experimental studies indicate that this variant causes decreased affinity for glucose-6-phosphate and a significant reduction of thermostability, affecting G6PD function (Gandomani MG, et. al., 2011).
• PM1: In a hotspot region, there are 4 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-154532989-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1068217.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-154532990-C-T is Pathogenic according to our data. Variant chrX-154532990-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2626309). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd4 at 3 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.1003G>A	p.Ala335Thr	missense	Exon 9 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.1093G>A	p.Ala365Thr	missense	Exon 9 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.1003G>A	p.Ala335Thr	missense	Exon 9 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.1003G>A	p.Ala335Thr	missense	Exon 9 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.1003G>A	p.Ala335Thr	missense	Exon 9 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.1141G>A	p.Ala381Thr	missense	Exon 9 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.0000798 AC: 9 AN: 112723 Hom.: 0 Cov.: 24

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: 0.00183

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000752

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000192 AC: 35 AN: 182482 AF XY: 0.000341

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000739

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000135 AC: 148 AN: 1098045 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 78 AN XY: 363445

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

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

South Asian (SAS) AF: 0.00170 AC: 92 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40393

Middle Eastern (MID) AF: 0.00218 AC: 9 AN: 4136

European-Non Finnish (NFE) AF: 0.0000356 AC: 30 AN: 842086

Other (OTH) AF: 0.000369 AC: 17 AN: 46094

GnomAD4 genome AF: 0.0000798 AC: 9 AN: 112778 Hom.: 0 Cov.: 24 AF XY: 0.0000859 AC XY: 3 AN XY: 34938

African (AFR) AF: 0.00 AC: 0 AN: 31141

American (AMR) AF: 0.00 AC: 0 AN: 10810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00183 AC: 5 AN: 2725

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53164

Other (OTH) AF: 0.00 AC: 0 AN: 1544

Alfa AF: 0.0000424 Hom.: 1

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	1	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (14)
7	-	-	not provided (7)
1	-	-	G6PD-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Malaria, susceptibility to (1)
1	-	-	Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (1)
-	-	-	G6PD CHATHAM (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.26	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.97
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.96	D
Vest4		0.51
MVP		0.99
MPC		1.8
ClinPred		0.077	T
GERP RS		5.8
Varity_R		0.81
gMVP		0.87
Mutation Taster		=72/28	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5030869; hg19: chrX-153761205;