1-155295550-CGAT-C

Position:

• chr1-155295550-CGAT-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000298.6(PKLR):​c.391_393del​(p.Ile131del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: PKLR NM_000298.6 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.23

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 13 ACMG points.

• PM1: In a helix (size 15) in uniprot entity KPYR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000298.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000298.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-155295550-CGAT-C is Pathogenic according to our data. Variant chr1-155295550-CGAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 292815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155295550-CGAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKLR	NM_000298.6	c.391_393del	p.Ile131del	inframe_deletion	4/11	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.391_393del	p.Ile131del	inframe_deletion	4/11	1	NM_000298.6	ENSP00000339933	P3
PKLR	ENST00000392414.7	c.298_300del	p.Ile100del	inframe_deletion	4/11	1		ENSP00000376214	A1
PKLR	ENST00000434082.3	c.199_201del	p.Ile67del	inframe_deletion	4/5	5		ENSP00000398037

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249026 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461628 Hom.: 0 AF XY: 0.0000509 AC XY: 37 AN XY: 727100

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: 0.0000692

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate kinase deficiency of red cells Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The PKLR c.391_393delATC (p.Ile131del) in-frame deletion variant has been reported in three studies in which it was found in a compound heterozygous state with a second variant in three individuals with pyruvate kinase deficiency (Baronciani et al. 1993; Baronciani et al. 1994; Baronciani et al. 1995). The p.Ile131del variant was also found in a heterozygous state in an unaffected parent of one of the probands. Control data are not reported for this variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. PK enzyme activity in red blood cells for individuals carrying the p.Ile131del variant was shown to be from 5.9% to 24.6% of wild type activity (Baronciani et al. 1995). Based on the evidence, the p.Ile131del variant is classified as likely pathogenic for pyruvate kinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 29, 2022

- -

Pyruvate kinase deficiency of red cells;C1863224:Pyruvate kinase hyperactivity Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs886045351; hg19: chr1-155265341;