X-154531643-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001360016.2(G6PD):c.*357G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 217,608 control chromosomes in the GnomAD database, including 44,702 homozygotes. There are 44,015 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.64 (19960 hom., 20634 hem., cov: 22)
  • Exomes 𝑓: 0.76 (24742 hom. 23381 hem.)
• Consequence: G6PD NM_001360016.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.00

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PD	NM_001360016.2	c.*357G>A		3_prime_UTR_variant	13/13	ENST00000393562.10
G6PD	NM_000402.4	c.*357G>A		3_prime_UTR_variant	13/13
G6PD	NM_001042351.3	c.*357G>A		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PD	ENST00000393562.10	c.*357G>A		3_prime_UTR_variant	13/13	1	NM_001360016.2	P4

Frequencies

GnomAD3 genomes AF: 0.641 AC: 70534 AN: 109963 Hom.: 19963 Cov.: 22 AF XY: 0.640 AC XY: 20614 AN XY: 32221

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.919

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 0.760 AC: 81727 AN: 107595 Hom.: 24742 Cov.: 1 AF XY: 0.718 AC XY: 23381 AN XY: 32581

Gnomad4 AFR exome AF: 0.0900

Gnomad4 AMR exome AF: 0.731

Gnomad4 ASJ exome AF: 0.706

Gnomad4 EAS exome AF: 0.855

Gnomad4 SAS exome AF: 0.576

Gnomad4 FIN exome AF: 0.898

Gnomad4 NFE exome AF: 0.845

Gnomad4 OTH exome AF: 0.733

GnomAD4 genome AF: 0.641 AC: 70540 AN: 110013 Hom.: 19960 Cov.: 22 AF XY: 0.639 AC XY: 20634 AN XY: 32281

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.727

Gnomad4 ASJ AF: 0.769

Gnomad4 EAS AF: 0.870

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.919

Gnomad4 NFE AF: 0.862

Gnomad4 OTH AF: 0.658

Alfa AF: 0.828 Hom.: 43571

Bravo AF: 0.618

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Dunham Lab, University of Washington

Aug 12, 2022

Variant found in hemizygote with deficiency and anemia (PP4). Decreased activity in red blood cells (8-23%) (PS3). Predicted to alter mRNA secondary structure and alter miRNA binding sites (PP3). Individuals with variant on 1311C>T/1365-13T>C haplotype have deficiency, some with anemia; this haplotype alone was found to have decreased G6PD activity (10-60%) (BP5). Frequency of 32.1% gnomAD2 and 35.9% gnomAD3 (BA1). Reported as benign by ARUP Laboratories and Invitae (BP6). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.084
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1050757; hg19: chrX-153759858;