rs185753709
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000298.6(PKLR):c.1511G>T(p.Arg504Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R504C) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Consequence
PKLR
NM_000298.6 missense
NM_000298.6 missense
Scores
13
4
Clinical Significance
Conservation
PhyloP100: 6.03
Publications
7 publications found
Genes affected
PKLR (HGNC:9020): (pyruvate kinase L/R) The protein encoded by this gene is a pyruvate kinase that catalyzes the transphosphorylation of phohsphoenolpyruvate into pyruvate and ATP, which is the rate-limiting step of glycolysis. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
PKLR Gene-Disease associations (from GenCC):
- pyruvate kinase deficiency of red cellsInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, ClinGen
- pyruvate kinase hyperactivityInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 17 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000298.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-155291864-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2663938.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.98056 (below the threshold of 3.09). Trascript score misZ: 1.5963 (below the threshold of 3.09). GenCC associations: The gene is linked to pyruvate kinase deficiency of red cells, pyruvate kinase hyperactivity.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932
PP5
Variant 1-155291863-C-A is Pathogenic according to our data. Variant chr1-155291863-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2431446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000298.6. You can select a different transcript below to see updated ACMG assignments.
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152100Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152100
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
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Gnomad AMR
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Gnomad ASJ
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Gnomad SAS
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Gnomad FIN
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Gnomad NFE
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Gnomad OTH
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GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome 0.0000131 AC: 2AN: 152218Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74416 show subpopulations
GnomAD4 genome
AF:
AC:
2
AN:
152218
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
74416
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41550
American (AMR)
AF:
AC:
2
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5168
South Asian (SAS)
AF:
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
AC:
0
AN:
67990
Other (OTH)
AF:
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
1
ClinVar
ClinVar submissions
View on ClinVar Significance:Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
not provided (1)
1
-
-
Pyruvate kinase deficiency of red cells (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PhyloP100
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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