NM_001360016.2:c.544C>T

Variant names:

• chrX-154534438-G-A
• rs267606836
• NM_001360016.2:c.544C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PM1 PP2

The NM_001360016.2(G6PD):​c.544C>T​(p.Arg182Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,209,651 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). ClinVar reports functional evidence for this variant: "SCV002599209: Undetectable activity or protein in red blood cells or leukocytes of hemizygote, and decreased activity in heterozygote (60%) (PS3).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R182Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• Publications: 10 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002599209: Undetectable activity or protein in red blood cells or leukocytes of hemizygote, and decreased activity in heterozygote (60%) (PS3).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001360016.2
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 185 curated pathogenic missense variants (we use a threshold of 10). The gene has 42 curated benign missense variants. Gene score misZ: 2.0008 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency, anemia, nonspherocytic hemolytic, due to G6PD deficiency.

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.544C>T	p.Arg182Trp	missense	Exon 6 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.634C>T	p.Arg212Trp	missense	Exon 6 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.544C>T	p.Arg182Trp	missense	Exon 6 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.544C>T	p.Arg182Trp	missense	Exon 6 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.544C>T	p.Arg182Trp	missense	Exon 6 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.544C>T	p.Arg182Trp	missense	Exon 6 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111792 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183118 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1097859 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363261

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.00 AC: 0 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40437

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841895

Other (OTH) AF: 0.00 AC: 0 AN: 46079

GnomAD4 genome AF: 0.00000895 AC: 1 AN: 111792 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34012

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30765

American (AMR) AF: 0.00 AC: 0 AN: 10657

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52913

Other (OTH) AF: 0.00 AC: 0 AN: 1503

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.9	L
PhyloP100		1.5
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.44	B
Vest4		0.58
MVP		0.96
MPC		0.30
ClinPred		0.35	T
GERP RS		2.6
Varity_R		0.49
gMVP		0.75
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs267606836; hg19: chrX-153762653;