rs3216174

Variant names:

• chrX-154534529-GA-G
• rs3216174
• NM_001360016.2:c.486-34delT

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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 -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 VariationId is 439744.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	NM_001360016.2	MANE Select	c.486-34delT		intron	N/A	NP_001346945.1
	G6PD	NM_000402.4		c.576-34delT		intron	N/A	NP_000393.4
	G6PD	NM_001042351.3		c.486-34delT		intron	N/A	NP_001035810.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.486-34delT		intron	N/A	ENSP00000377192.3
	G6PD	ENST00000696421.1		c.486-34delT		intron	N/A	ENSP00000512616.1
	G6PD	ENST00000369620.6	TSL:5	c.486-34delT		intron	N/A	ENSP00000358633.2

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 398 AN: 112098 Hom.: 12 Cov.: 23

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

GnomAD2 exomes AF: 0.00889 AC: 1586 AN: 178413 AF XY: 0.00758

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26356

American (AMR) AF: 0.000284 AC: 10 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.000258 AC: 5 AN: 19367

East Asian (EAS) AF: 0.0964 AC: 2909 AN: 30189

South Asian (SAS) AF: 0.000999 AC: 54 AN: 54051

European-Finnish (FIN) AF: 0.0123 AC: 462 AN: 37654

Middle Eastern (MID) AF: 0.000732 AC: 3 AN: 4097

European-Non Finnish (NFE) AF: 0.000241 AC: 203 AN: 840607

Other (OTH) AF: 0.00479 AC: 220 AN: 45977

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

African (AFR) AF: 0.0000647 AC: 2 AN: 30908

American (AMR) AF: 0.00 AC: 0 AN: 10712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.0846 AC: 297 AN: 3510

South Asian (SAS) AF: 0.00146 AC: 4 AN: 2732

European-Finnish (FIN) AF: 0.0119 AC: 74 AN: 6207

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000283 AC: 15 AN: 53000

Other (OTH) AF: 0.00261 AC: 4 AN: 1534

Alfa AF: 0.00127 Hom.: 9

Bravo AF: 0.00418

Asia WGS AF: 0.0290 AC: 72 AN: 2522

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3216174; hg19: chrX-153762744; COSMIC: COSV107472158; COSMIC: COSV107472158;