Genetic Variant NM_000298.6:c.1529G>T (chr1-155291845-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000298.6(PKLR):c.1529G>T(p.Arg510Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R510Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PKLR
NM_000298.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.75

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 chr1-155291845-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKLR	NM_000298.6 link	c.1529G>T	p.Arg510Leu	missense_variant	Exon 10 of 11	ENST00000342741.6	NP_000289.1	P30613-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6 link	c.1529G>T	p.Arg510Leu	missense_variant	Exon 10 of 11	1	NM_000298.6	ENSP00000339933.4		P30613-1
PKLR	ENST00000392414.7 link	c.1436G>T	p.Arg479Leu	missense_variant	Exon 10 of 11	1		ENSP00000376214.3		P30613-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.049

D;T

Polyphen

0.98

D;.

Vest4

0.89

MutPred

0.89

Loss of MoRF binding (P = 0.0312);.;

MVP

0.97

MPC

1.4

ClinPred

1.0

GERP RS

4.8

Varity_R

0.97

gMVP

0.99

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over