G6PD p.Val394Leu

Variant names:

• chrX-154532674-C-A
• NM_001360016.2:c.1180G>T
• G6PD p.Val394Leu

Your query was ambiguous. Multiple possible variants found:

• chrX-154532674-C-A
• chrX-154532674-C-G
• chrX-154532672-CAC-TAA
• chrX-154532672-CAC-AAG
• chrX-154532672-CAC-GAG
• chrX-154532672-CAC-TAG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS1 PM1 PM2 PP2 PP3_Strong

The NM_001360016.2(G6PD):​c.1180G>T​(p.Val394Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V394V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 25)
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.36
• 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: Ambry Genetics, ClinGen, 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 13 ACMG points.

• PS1: Transcript NM_001360016.2 (G6PD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001360016.2
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

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.1180G>T	p.Val394Leu	missense	Exon 10 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.1270G>T	p.Val424Leu	missense	Exon 10 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.1180G>T	p.Val394Leu	missense	Exon 10 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.1180G>T	p.Val394Leu	missense	Exon 10 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.1180G>T	p.Val394Leu	missense	Exon 10 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.1318G>T	p.Val440Leu	missense	Exon 10 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.94	L
PhyloP100		7.4
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.78
Sift	Benign	0.31	T
Sift4G	Benign	0.26	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.79
gMVP		0.96
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-153760889;