1-155290305-G-A

Position:

• chr1-155290305-G-A

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.*267C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 517,590 control chromosomes in the GnomAD database, including 30,088 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10488 hom., cov: 31)
  • Exomes 𝑓: 0.30 (19600 hom.)
• Consequence: PKLR NM_000298.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.578

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=-0.84).
• BP6: Variant 1-155290305-G-A is Benign according to our data. Variant chr1-155290305-G-A is described in ClinVar as [Benign]. Clinvar id is 292802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155290305-G-A is described in Lovd as [Benign]. Variant chr1-155290305-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKLR	NM_000298.6	c.*267C>T		3_prime_UTR_variant	11/11	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.*267C>T		3_prime_UTR_variant	11/11	1	NM_000298.6	ENSP00000339933	P3
PKLR	ENST00000392414.7	c.*267C>T		3_prime_UTR_variant	11/11	1		ENSP00000376214	A1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53375 AN: 151902 Hom.: 10453 Cov.: 31

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.335

GnomAD4 exome AF: 0.299 AC: 109331 AN: 365570 Hom.: 19600 Cov.: 0 AF XY: 0.298 AC XY: 56945 AN XY: 191342

Gnomad4 AFR exome AF: 0.491

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.211

Gnomad4 EAS exome AF: 0.715

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.283

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.292

GnomAD4 genome AF: 0.352 AC: 53461 AN: 152020 Hom.: 10488 Cov.: 31 AF XY: 0.354 AC XY: 26344 AN XY: 74316

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.701

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.331

Alfa AF: 0.274 Hom.: 5998

Bravo AF: 0.364

Asia WGS AF: 0.540 AC: 1877 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.84
CADD	Benign	3.5
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs932972; hg19: chr1-155260096;