rs1557230370

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BS2_Supporting

The NM_001360016.2(G6PD):c.574C>T(p.Arg192Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,097,395 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000012 ( 0 hom. 6 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.248

Publications

0 publications found

Variant links:

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

G6PD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 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 anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
G6PD	NM_001360016.2 link	c.574C>T	p.Arg192Cys	missense_variant	Exon 6 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4 link	c.664C>T	p.Arg222Cys	missense_variant	Exon 6 of 13		NP_000393.4
G6PD	NM_001042351.3 link	c.574C>T	p.Arg192Cys	missense_variant	Exon 6 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10 link	c.574C>T	p.Arg192Cys	missense_variant	Exon 6 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183252

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1097395

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

362791

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26396

American (AMR)

AF:

0.0000284

AC:

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

54126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

841424

Other (OTH)

AF:

0.0000217

AC:

AN:

46074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency

Uncertain:1

Feb 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the G6PD protein (p.Arg192Cys). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with G6PD-related conditions. ClinVar contains an entry for this variant (Variation ID: 537706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PD protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;D;D;.;D;.;D

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.0

.;.;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.54

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Uncertain

2.7

M;M;M;M;.;.;.

PhyloP100

0.25

PrimateAI

Benign

0.25

PROVEAN

Benign

0.0

.;.;D;D;D;D;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;D;D;D;D;D

Sift4G

Uncertain

0.049

D;.;D;D;.;.;.

Vest4

0.29

ClinPred

0.72

GERP RS

3.9

Varity_R

0.30

gMVP

0.88

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over