rs137852344

Variant names:

• chrX-154532245-G-C
• rs137852344
• NM_001360016.2:c.1400C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-154532245-G-C
• chrX-154532245-G-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001360016.2(G6PD):​c.1400C>G​(p.Pro467Arg) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: G6PD NM_001360016.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.30
• Publications: 4 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 17 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 anemia, nonspherocytic hemolytic, due to G6PD deficiency, class I glucose-6-phosphate dehydrogenase deficiency, G6PD deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-154532245-G-C is Pathogenic according to our data. Variant chrX-154532245-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 10409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1400C>G	p.Pro467Arg	missense	Exon 12 of 13	NP_001346945.1	A0A384NL00
	G6PD	NM_000402.4		c.1490C>G	p.Pro497Arg	missense	Exon 12 of 13	NP_000393.4	P11413-3
	G6PD	NM_001042351.3		c.1400C>G	p.Pro467Arg	missense	Exon 12 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.1400C>G	p.Pro467Arg	missense	Exon 12 of 13	ENSP00000377192.3	P11413-1
	G6PD	ENST00000696421.1		c.1400C>G	p.Pro467Arg	missense	Exon 12 of 13	ENSP00000512616.1	A0A8Q3SIS5
	G6PD	ENST00000369620.6	TSL:5	c.1538C>G	p.Pro513Arg	missense	Exon 12 of 13	ENSP00000358633.2	P11413-2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 182466 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1098016 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 1 AN XY: 363414

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35195

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40427

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842051

Other (OTH) AF: 0.00 AC: 0 AN: 46093

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Anemia, nonspherocytic hemolytic, due to G6PD deficiency (3)
-	-	-	G6PD NEAPOLIS (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.92		Gain of MoRF binding (P = 0.004)
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.98
Mutation Taster		=2/98	disease causing

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: rs137852344; hg19: chrX-153760460;