X-154532765-G-C

Variant names:

• chrX-154532765-G-C
• rs137852329
• NM_001360016.2:c.1089C>G

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001360016.2(G6PD):​c.1089C>G​(p.Asn363Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N363I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.21
• Publications: 5 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: Pathogenic. The variant received 25 ACMG points.

• PS1: Transcript NM_001360016.2 (G6PD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 10390
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-154532766-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876
• PP5: Variant X-154532765-G-C is Pathogenic according to our data. Variant chrX-154532765-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
G6PD	NM_001360016.2	c.1089C>G	p.Asn363Lys	missense_variant	Exon 10 of 13	ENST00000393562.10	NP_001346945.1
G6PD	NM_000402.4	c.1179C>G	p.Asn393Lys	missense_variant	Exon 10 of 13		NP_000393.4
G6PD	NM_001042351.3	c.1089C>G	p.Asn363Lys	missense_variant	Exon 10 of 13		NP_001035810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
G6PD	ENST00000393562.10	c.1089C>G	p.Asn363Lys	missense_variant	Exon 10 of 13	1	NM_001360016.2	ENSP00000377192.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jul 30, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1

Aug 12, 2022

Dunham Lab, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Variant found in hemizygotes with G6PD deficiency and anemia (PP4). Inherited with deficiency through five generations in one family (PP1). Decreased activity in red blood cells (3-30%) (PS3). Not found in gnomAD (PM2). Leads to same amino acid change as pathogenic variant (ClinVar ID 10390) (PS1). Post_P 0.999 (odds of pathogenicity 6551, Prior_P 0.1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	0.38
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.97	D;D;D;.
FATHMM_MKL	Benign	0.27	N
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	M;M;M;.
PhyloP100		-1.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.3	.;.;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0070	.;.;D;D
Sift4G	Uncertain	0.011	D;.;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.81
MutPred		0.76		Gain of MoRF binding (P = 0.0364);Gain of MoRF binding (P = 0.0364);Gain of MoRF binding (P = 0.0364);.;
MVP		0.96
MPC		2.2
ClinPred		0.99	D
GERP RS		-6.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs137852329; hg19: chrX-153760980;