X-154534440-T-A

Variant names:

• chrX-154534440-T-A
• rs5030872
• NM_001360016.2:c.542A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 11P and 2B. PM1 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_000402.4(G6PD):​c.632A>T​(p.Asp211Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000777 in 1,209,769 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.000041 (0 hom. 15 hem.)
• Consequence: G6PD NM_000402.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.78
• Publications: 56 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 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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.
• PP5: Variant X-154534440-T-A is Pathogenic according to our data. Variant chrX-154534440-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16829187). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Hemizygotes in GnomAd4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	NM_001360016.2	MANE Select	c.542A>T	p.Asp181Val	missense	Exon 6 of 13	NP_001346945.1
	G6PD	NM_000402.4		c.632A>T	p.Asp211Val	missense	Exon 6 of 13	NP_000393.4
	G6PD	NM_001042351.3		c.542A>T	p.Asp181Val	missense	Exon 6 of 13	NP_001035810.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.542A>T	p.Asp181Val	missense	Exon 6 of 13	ENSP00000377192.3
	G6PD	ENST00000696421.1		c.542A>T	p.Asp181Val	missense	Exon 6 of 13	ENSP00000512616.1
	G6PD	ENST00000369620.6	TSL:5	c.542A>T	p.Asp181Val	missense	Exon 6 of 13	ENSP00000358633.2

Frequencies

GnomAD3 genomes AF: 0.000438 AC: 49 AN: 111781 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00103

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000136 AC: 25 AN: 183162 AF XY: 0.000103

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000410 AC: 45 AN: 1097988 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 15 AN XY: 363384

African (AFR) AF: 0.000871 AC: 23 AN: 26402

American (AMR) AF: 0.000313 AC: 11 AN: 35195

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40452

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841983

Other (OTH) AF: 0.000174 AC: 8 AN: 46089

GnomAD4 genome AF: 0.000438 AC: 49 AN: 111781 Hom.: 0 Cov.: 23 AF XY: 0.000206 AC XY: 7 AN XY: 33999

African (AFR) AF: 0.00124 AC: 38 AN: 30751

American (AMR) AF: 0.00103 AC: 11 AN: 10657

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00 AC: 0 AN: 2681

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52931

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.0000754 Hom.: 1

Bravo AF: 0.000536

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (4)
1	-	-	G6PD deficiency (1)
1	-	-	Malaria, susceptibility to (1)
-	-	-	G6PD MALAGA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	-0.29	N
PhyloP100		7.8
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.61
Sift	Benign	0.073	T
Sift4G	Benign	0.16	T
Polyphen		0.0080	B
Vest4		0.68
MVP		1.0
MPC		0.29
ClinPred		0.057	T
GERP RS		5.7
Varity_R		0.71
gMVP		0.80
Mutation Taster		=59/41	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: rs5030872; hg19: chrX-153762655;