chrX-154531643-C-T

Variant names:

• chrX-154531643-C-T
• rs1050757
• NM_001360016.2:c.*357G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 24 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.*357G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.*357G>A		3_prime_UTR_variant	Exon 13 of 13		NP_000393.4
G6PD	NM_001042351.3	c.*357G>A		3_prime_UTR_variant	Exon 13 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.*357G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes AF: 0.641 AC: 70534 AN: 109963 Hom.: 19963 Cov.: 22

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

African (AFR) AF: 0.0900 AC: 473 AN: 5255

American (AMR) AF: 0.731 AC: 3822 AN: 5231

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 1905 AN: 2699

East Asian (EAS) AF: 0.855 AC: 4014 AN: 4695

South Asian (SAS) AF: 0.576 AC: 8152 AN: 14152

European-Finnish (FIN) AF: 0.898 AC: 5130 AN: 5712

Middle Eastern (MID) AF: 0.537 AC: 235 AN: 438

European-Non Finnish (NFE) AF: 0.845 AC: 53559 AN: 63362

Other (OTH) AF: 0.733 AC: 4437 AN: 6051

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

African (AFR) AF: 0.150 AC: 4587 AN: 30584

American (AMR) AF: 0.727 AC: 7594 AN: 10439

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2010 AN: 2615

East Asian (EAS) AF: 0.870 AC: 2974 AN: 3419

South Asian (SAS) AF: 0.524 AC: 1369 AN: 2612

European-Finnish (FIN) AF: 0.919 AC: 5214 AN: 5676

Middle Eastern (MID) AF: 0.699 AC: 151 AN: 216

European-Non Finnish (NFE) AF: 0.862 AC: 45067 AN: 52283

Other (OTH) AF: 0.658 AC: 988 AN: 1501

Alfa AF: 0.760 Hom.: 44677

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

Aug 12, 2022

Dunham Lab, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

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
PhyloP100		-1.0
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

Other links and lift over

dbSNP: rs1050757; hg19: chrX-153759858;