1-155300271-C-T

Position:

• chr1-155300271-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000342741.6(PKLR):​c.110G>A​(p.Gly37Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,044 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G37G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PKLR ENST00000342741.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.29

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKLR	NM_000298.6	c.110G>A	p.Gly37Glu	missense_variant	2/11	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.110G>A	p.Gly37Glu	missense_variant	2/11	1	NM_000298.6	ENSP00000339933	P3
PKLR	ENST00000392414.7	c.17G>A	p.Gly6Glu	missense_variant	2/11	1		ENSP00000376214	A1
PKLR	ENST00000434082.3	c.-21-62G>A		intron_variant		5		ENSP00000398037

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439044 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 714310

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: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pyruvate kinase hyperactivity Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1965

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.16	N
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.13	A;A
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.97	N;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.22	T;T
Polyphen		0.92	P;.
Vest4		0.52
MutPred		0.74		Loss of sheet (P = 0.0315);.;
MVP		0.98
MPC		1.5
ClinPred		0.78	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.82

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: rs118204087; hg19: chr1-155270062;