NM_001360016.2:c.376A>G

Variant names:

• chrX-154535277-T-C
• rs1050829
• NM_001360016.2:c.376A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BA1

The NM_001360016.2(G6PD):​c.376A>G​(p.Asn126Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,210,053 control chromosomes in the GnomAD database, including 2,270 homozygotes. There are 5,488 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N126Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.091 (1131 hom., 2718 hem., cov: 23)
  • Exomes 𝑓: 0.0096 (1139 hom. 2770 hem.)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:6 B:6 O:2
• Conservation: PhyloP100: -0.123
• Publications: 247 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.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 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 anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005546838).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 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.376A>G	p.Asn126Asp	missense	Exon 5 of 13	NP_001346945.1
	G6PD	NM_000402.4		c.466A>G	p.Asn156Asp	missense	Exon 5 of 13	NP_000393.4
	G6PD	NM_001042351.3		c.376A>G	p.Asn126Asp	missense	Exon 5 of 13	NP_001035810.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PD	ENST00000393562.10	TSL:1 MANE Select	c.376A>G	p.Asn126Asp	missense	Exon 5 of 13	ENSP00000377192.3
	G6PD	ENST00000696421.1		c.376A>G	p.Asn126Asp	missense	Exon 5 of 13	ENSP00000512616.1
	G6PD	ENST00000369620.6	TSL:5	c.376A>G	p.Asn126Asp	missense	Exon 5 of 13	ENSP00000358633.2

Frequencies

GnomAD3 genomes AF: 0.0907 AC: 10141 AN: 111861 Hom.: 1130 Cov.: 23

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000886

Gnomad OTH AF: 0.0673

GnomAD2 exomes AF: 0.0257 AC: 4704 AN: 183378 AF XY: 0.0161

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000647

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00958 AC: 10515 AN: 1098138 Hom.: 1139 Cov.: 31 AF XY: 0.00762 AC XY: 2770 AN XY: 363494

African (AFR) AF: 0.325 AC: 8593 AN: 26401

American (AMR) AF: 0.0168 AC: 592 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.000609 AC: 33 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.0119 AC: 49 AN: 4127

European-Non Finnish (NFE) AF: 0.000372 AC: 313 AN: 842048

Other (OTH) AF: 0.0203 AC: 934 AN: 46089

GnomAD4 genome AF: 0.0907 AC: 10153 AN: 111915 Hom.: 1131 Cov.: 23 AF XY: 0.0797 AC XY: 2718 AN XY: 34121

African (AFR) AF: 0.313 AC: 9597 AN: 30652

American (AMR) AF: 0.0380 AC: 405 AN: 10651

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.000739 AC: 2 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6211

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.000886 AC: 47 AN: 53054

Other (OTH) AF: 0.0665 AC: 101 AN: 1519

Alfa AF: 0.0461 Hom.: 2299

Bravo AF: 0.103

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.312 AC: 1195

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.0286 AC: 3471

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
11	2	2	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (16)
3	4	1	not provided (8)
2	-	-	Malaria, susceptibility to;C2720289:Anemia, nonspherocytic hemolytic, due to G6PD deficiency (2)
1	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency;C2939465:G6PD deficiency (1)
-	-	1	G6PD deficiency (1)
-	-	1	Glomerulopathy with fibronectin deposits 2 (1)
1	-	-	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	-	G6PD A+ (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	1.7
DANN	Benign	0.90
DEOGEN2	Uncertain	0.69	D
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.54	N
PhyloP100		-0.12
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.27
Sift	Benign	0.24	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.15
MPC		0.20
ClinPred		0.00071	T
GERP RS		0.49
Varity_R		0.28
gMVP		0.47
Mutation Taster		=94/6	disease causing (ClinVar)

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: rs1050829; hg19: chrX-153763492; COSMIC: COSV63703563; COSMIC: COSV63703563;