X-154531480-C-T

Variant names:

• chrX-154531480-C-T
• rs782764609
• NM_001360016.2:c.*520G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_001360016.2(G6PD):​c.*520G>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 0.000992 in 130,037 control chromosomes in the GnomAD database, including 1 homozygotes. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., 40 hem., cov: 23)
  • Exomes 𝑓: 0.00061 (0 hom. 3 hem.)
• Consequence: G6PD NM_001360016.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.06
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant X-154531480-C-T is Benign according to our data. Variant chrX-154531480-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 368094.
• BS2: High Hemizygotes in GnomAd4 at 40 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	NM_001360016.2	MANE Select	c.*520G>A		3_prime_UTR	Exon 13 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.*520G>A		3_prime_UTR	Exon 13 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.*520G>A		3_prime_UTR	Exon 13 of 13	NP_001035810.1	P11413-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.*520G>A		3_prime_UTR	Exon 13 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000915896.1		c.*520G>A		3_prime_UTR	Exon 13 of 13	ENSP00000585955.1
	G6PD	ENST00000439227.6	TSL:5	c.*520G>A		3_prime_UTR	Exon 13 of 13	ENSP00000395599.2	E7EUI8

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 118 AN: 112065 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000614 AC: 11 AN: 17921 Hom.: 0 Cov.: 0 AF XY: 0.000863 AC XY: 3 AN XY: 3475

African (AFR) AF: 0.00 AC: 0 AN: 451

American (AMR) AF: 0.000898 AC: 2 AN: 2227

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 4 AN: 280

East Asian (EAS) AF: 0.00 AC: 0 AN: 733

South Asian (SAS) AF: 0.00 AC: 0 AN: 1615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 835

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.000372 AC: 4 AN: 10739

Other (OTH) AF: 0.000993 AC: 1 AN: 1007

GnomAD4 genome AF: 0.00105 AC: 118 AN: 112116 Hom.: 1 Cov.: 23 AF XY: 0.00117 AC XY: 40 AN XY: 34320

African (AFR) AF: 0.000129 AC: 4 AN: 30916

American (AMR) AF: 0.00406 AC: 43 AN: 10591

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 65 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6145

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53104

Other (OTH) AF: 0.00 AC: 0 AN: 1525

Alfa AF: 0.00108 Hom.: 6

Bravo AF: 0.00133

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	G6PD deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.067
DANN	Benign	0.41
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs782764609; hg19: chrX-153759695;