rs118204089

chr1-155295555-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000298.6(PKLR):c.389C>A(p.Ser130Tyr) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S130P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKLR NM_000298.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 15) in uniprot entity KPYR_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) 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 chr1-155295556-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 1-155295555-G-T is Pathogenic according to our data. Variant chr1-155295555-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1514.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-155295555-G-T is described in UniProt as null. Variant chr1-155295555-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKLR	NM_000298.6	c.389C>A	p.Ser130Tyr	missense_variant	4/11	ENST00000342741.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKLR	ENST00000342741.6	c.389C>A	p.Ser130Tyr	missense_variant	4/11	1	NM_000298.6	P3
PKLR	ENST00000392414.7	c.296C>A	p.Ser99Tyr	missense_variant	4/11	1		A1
PKLR	ENST00000434082.3	c.197C>A	p.Ser66Tyr	missense_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pyruvate kinase deficiency of red cells Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.011	D;D;.
Sift4G	Uncertain	0.0090	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.58
MutPred		0.84		Loss of disorder (P = 0.0178);.;.;
MVP		0.99
MPC		1.4
ClinPred		0.98	D
GERP RS		3.3
Varity_R		0.78
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs118204089; hg19: chr1-155265346;