rs2515904

Positions:

• chrX-154534556-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001360016.2(G6PD):​c.486-60C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00843 in 1,185,278 control chromosomes in the GnomAD database, including 544 homozygotes. There are 2,656 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (258 hom., 1307 hem., cov: 23)
  • Exomes 𝑓: 0.0048 (286 hom. 1349 hem.)
• Consequence: G6PD NM_001360016.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: -0.00100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-154534556-G-C is Benign according to our data. Variant chrX-154534556-G-C is described in ClinVar as [Benign]. Clinvar id is 10374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154534556-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.486-60C>G		intron_variant		ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.576-60C>G		intron_variant			NP_000393.4
G6PD	NM_001042351.3	c.486-60C>G		intron_variant			NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.486-60C>G		intron_variant		1	NM_001360016.2	ENSP00000377192	P4

Frequencies

GnomAD3 genomes AF: 0.0433 AC: 4845 AN: 111849 Hom.: 258 Cov.: 23 AF XY: 0.0382 AC XY: 1300 AN XY: 34033

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000367

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.0351

GnomAD4 exome AF: 0.00478 AC: 5133 AN: 1073378 Hom.: 286 AF XY: 0.00393 AC XY: 1349 AN XY: 343300

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.00644

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000356

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.00959

GnomAD4 genome AF: 0.0434 AC: 4854 AN: 111900 Hom.: 258 Cov.: 23 AF XY: 0.0383 AC XY: 1307 AN XY: 34094

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000368

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000283

Gnomad4 OTH AF: 0.0347

Alfa AF: 0.0352 Hom.: 113

Bravo AF: 0.0492

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

G6PD deficiency Pathogenic:1 Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_009015.2(NM_001042351.2):c.486-60C>G in the gene G6PD has an allele frequency of 0.155 in African subpopulation in the gnomAD database. A total of 43 homozygous and 316 hemizygotes occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 28, 1979	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.58
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2515904; hg19: chrX-153762771;