rs3216174

Positions:

• chrX-154534529-GA-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001360016.2(G6PD):​c.486-34delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,205,636 control chromosomes in the GnomAD database, including 130 homozygotes. There are 1,325 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (12 hom., 148 hem., cov: 23)
  • Exomes 𝑓: 0.0035 (118 hom. 1177 hem.)
• Consequence: G6PD NM_001360016.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.169

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 -9 ACMG points.

• BP6: Variant X-154534529-GA-G is Benign according to our data. Variant chrX-154534529-GA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439744.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.486-34delT		intron_variant		ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.576-34delT		intron_variant			NP_000393.4
G6PD	NM_001042351.3	c.486-34delT		intron_variant			NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.486-34delT		intron_variant		1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 398 AN: 112098 Hom.: 12 Cov.: 23 AF XY: 0.00429 AC XY: 147 AN XY: 34280

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0852

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.00198

GnomAD3 exomes AF: 0.00889 AC: 1586 AN: 178413 Hom.: 48 AF XY: 0.00758 AC XY: 491 AN XY: 64805

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.0950

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00354 AC: 3866 AN: 1093484 Hom.: 118 Cov.: 32 AF XY: 0.00327 AC XY: 1177 AN XY: 360014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.000258

Gnomad4 EAS exome AF: 0.0964

Gnomad4 SAS exome AF: 0.000999

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.000241

Gnomad4 OTH exome AF: 0.00479

GnomAD4 genome AF: 0.00353 AC: 396 AN: 112152 Hom.: 12 Cov.: 23 AF XY: 0.00431 AC XY: 148 AN XY: 34344

Gnomad4 AFR AF: 0.0000647

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0846

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.000283

Gnomad4 OTH AF: 0.00261

Alfa AF: 0.00127 Hom.: 9

Bravo AF: 0.00418

Asia WGS AF: 0.0290 AC: 72 AN: 2522

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	curation	Dunham Lab, University of Washington	Aug 12, 2022	Variant found in unrelated hemizygotes with deficiency (PS4_M, PP4). Decreased activity in red blood cells (PS3). Reported as benign by multiple clinical testing groups (BP6). Post_P 0.89997 (odds of pathogenicity 80.97, Prior_P 0.1). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 20, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

This variant is associated with the following publications: (PMID: 30077011, 26829728) -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs3216174; hg19: chrX-153762744;