rs5030869

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001360016.2(G6PD):​c.1003G>T​(p.Ala335Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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: not found (cov: 24)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.969
• Publications: 57 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: Likely_pathogenic. The variant received 7 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, 5 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• 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 anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1003G>T	p.Ala335Ser	missense_variant	Exon 9 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1093G>T	p.Ala365Ser	missense_variant	Exon 9 of 13		NP_000393.4
G6PD	NM_001042351.3	c.1003G>T	p.Ala335Ser	missense_variant	Exon 9 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1003G>T	p.Ala335Ser	missense_variant	Exon 9 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000548 AC: 1 AN: 182482 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: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;D;D;.;D
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.96	.;.;D;D;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.5	L;L;L;.;.
PhyloP100		0.97
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.63	.;.;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	.;.;D;D;D
Sift4G	Uncertain	0.0030	D;.;D;D;.
Polyphen		0.10	B;B;B;.;.
Vest4		0.43
MutPred		0.66		Gain of glycosylation at A335 (P = 0.0103);Gain of glycosylation at A335 (P = 0.0103);Gain of glycosylation at A335 (P = 0.0103);.;.;
MVP		0.89
MPC		1.7
ClinPred		0.55	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.85
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;