1-155290559-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000298.6(PKLR):c.*13T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,523,606 control chromosomes in the GnomAD database, including 71,590 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10464 hom., cov: 30)
  • Exomes 𝑓: 0.28 (61126 hom.)
• Consequence: PKLR NM_000298.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.833

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-155290559-A-G is Benign according to our data. Variant chr1-155290559-A-G is described in ClinVar as [Benign]. Clinvar id is 255797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155290559-A-G is described in Lovd as [Benign]. Variant chr1-155290559-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKLR	NM_000298.6	c.*13T>C		3_prime_UTR_variant	11/11	ENST00000342741.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKLR	ENST00000342741.6	c.*13T>C		3_prime_UTR_variant	11/11	1	NM_000298.6	P3
PKLR	ENST00000392414.7	c.*13T>C		3_prime_UTR_variant	11/11	1		A1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53280 AN: 151534 Hom.: 10429 Cov.: 30

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.335 AC: 83360 AN: 248570 Hom.: 15928 AF XY: 0.325 AC XY: 43728 AN XY: 134586

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.700

Gnomad SAS exome AF: 0.332

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.283 AC: 387637 AN: 1371954 Hom.: 61126 Cov.: 23 AF XY: 0.282 AC XY: 193580 AN XY: 687444

Gnomad4 AFR exome AF: 0.489

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.724

Gnomad4 SAS exome AF: 0.325

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.298

GnomAD4 genome AF: 0.352 AC: 53367 AN: 151652 Hom.: 10464 Cov.: 30 AF XY: 0.355 AC XY: 26265 AN XY: 74084

Gnomad4 AFR AF: 0.492

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.702

Gnomad4 SAS AF: 0.341

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.330

Alfa AF: 0.261 Hom.: 5688

Bravo AF: 0.364

Asia WGS AF: 0.539 AC: 1876 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 19, 2022	- -

Pyruvate kinase deficiency of red cells Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	3.1
Dann	Benign	0.69

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: rs1052177; hg19: chr1-155260350;