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rs1050829

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001360016.2(G6PD):c.376A>T(p.Asn126Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,210,012 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD Genomes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N126D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.000031 ( 0 hom. 7 hem. )

Consequence

G6PD
NM_001360016.2 missense

Scores

3
4
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: -0.123
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001360016.2
BP4
Computational evidence support a benign effect (MetaRNN=0.14649871).
BS2
High Hemizygotes in GnomAdExome at 8 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
G6PDNM_001360016.2 linkuse as main transcriptc.376A>T p.Asn126Tyr missense_variant 5/13 ENST00000393562.10
G6PDNM_000402.4 linkuse as main transcriptc.466A>T p.Asn156Tyr missense_variant 5/13
G6PDNM_001042351.3 linkuse as main transcriptc.376A>T p.Asn126Tyr missense_variant 5/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
G6PDENST00000393562.10 linkuse as main transcriptc.376A>T p.Asn126Tyr missense_variant 5/131 NM_001360016.2 P4P11413-1

Frequencies

GnomAD3 genomes
AF:
0.0000179
AC:
2
AN:
111874
Hom.:
0
Cov.:
23
AF XY:
0.0000294
AC XY:
1
AN XY:
34062
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000188
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
GnomAD3 exomes
AF:
0.000175
AC:
32
AN:
183378
Hom.:
0
AF XY:
0.000118
AC XY:
8
AN XY:
67872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00113
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.0000310
AC:
34
AN:
1098138
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
7
AN XY:
363494
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000937
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
AF:
0.0000179
AC:
2
AN:
111874
Hom.:
0
Cov.:
23
AF XY:
0.0000294
AC XY:
1
AN XY:
34062
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000188
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000907
ExAC
AF:
0.000115
AC:
14

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityApr 17, 2023- -
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 16, 2024- -
Likely pathogenic, criteria provided, single submittercurationDunham Lab, University of WashingtonAug 12, 2022Variant found in hemizygote with G6PD deficiency (PP4). Decreased activity in red blood cells of hemizygote (47%) (PS3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.949 (odds of pathogenicity 168.4, Prior_P 0.1). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
-0.020
Cadd
Benign
14
Dann
Uncertain
0.97
DEOGEN2
Pathogenic
0.88
D;D;D;.;D;.;D
FATHMM_MKL
Benign
0.34
N
M_CAP
Pathogenic
0.29
D
MetaRNN
Benign
0.15
T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.8
M;M;M;M;.;.;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.39
T
Sift4G
Uncertain
0.015
D;.;D;D;.;.;.
Polyphen
0.34
B;B;B;.;.;.;.
Vest4
0.34
MutPred
0.52
Loss of disorder (P = 0.044);Loss of disorder (P = 0.044);Loss of disorder (P = 0.044);Loss of disorder (P = 0.044);Loss of disorder (P = 0.044);Loss of disorder (P = 0.044);Loss of disorder (P = 0.044);
MVP
0.94
MPC
0.29
ClinPred
0.13
T
GERP RS
0.49
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.38
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1050829; hg19: chrX-153763492; API