1-155290592-G-T

Position:

chr1-155290592-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000298.6(PKLR):c.1705C>A(p.Arg569=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,605,358 control chromosomes in the GnomAD database, including 77,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10448 hom., cov: 30)

Exomes 𝑓: 0.29 ( 66956 hom. )

Consequence

PKLR
NM_000298.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 1-155290592-G-T is Benign according to our data. Variant chr1-155290592-G-T is described in ClinVar as [Benign]. Clinvar id is 255798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155290592-G-T is described in Lovd as [Benign]. Variant chr1-155290592-G-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=3.08 with no splicing effect.

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 linkuse as main transcript	c.1705C>A	p.Arg569=	synonymous_variant	11/11	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6 linkuse as main transcript	c.1705C>A	p.Arg569=	synonymous_variant	11/11	1	NM_000298.6	ENSP00000339933	P3	P30613-1
PKLR	ENST00000392414.7 linkuse as main transcript	c.1612C>A	p.Arg538=	synonymous_variant	11/11	1		ENSP00000376214	A1	P30613-2

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53260

AN:

151634

Hom.:

10413

Cov.:

show subpopulations

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:

0.341

Gnomad FIN

AF:

0.318

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.262

Gnomad OTH

AF:

0.334

GnomAD3 exomes

AF:

0.337

AC:

84394

AN:

250236

Hom.:

16297

AF XY:

0.326

AC XY:

44188

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.499

Gnomad AMR exome

AF:

0.411

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.702

Gnomad SAS exome

AF:

0.333

Gnomad FIN exome

AF:

0.311

Gnomad NFE exome

AF:

0.251

Gnomad OTH exome

AF:

0.300

GnomAD4 exome

AF:

0.289

AC:

419413

AN:

1453606

Hom.:

66956

Cov.:

AF XY:

0.287

AC XY:

207575

AN XY:

723622

show subpopulations

Gnomad4 AFR exome

AF:

0.496

Gnomad4 AMR exome

AF:

0.406

Gnomad4 ASJ exome

AF:

0.222

Gnomad4 EAS exome

AF:

0.724

Gnomad4 SAS exome

AF:

0.328

Gnomad4 FIN exome

AF:

0.304

Gnomad4 NFE exome

AF:

0.259

Gnomad4 OTH exome

AF:

0.304

GnomAD4 genome

AF:

0.352

AC:

53347

AN:

151752

Hom.:

10448

Cov.:

AF XY:

0.354

AC XY:

26252

AN XY:

74134

show subpopulations

Gnomad4 AFR

AF:

0.491

Gnomad4 AMR

AF:

0.334

Gnomad4 ASJ

AF:

0.211

Gnomad4 EAS

AF:

0.701

Gnomad4 SAS

AF:

0.341

Gnomad4 FIN

AF:

0.318

Gnomad4 NFE

AF:

0.262

Gnomad4 OTH

AF:

0.330

Alfa

AF:

0.258

Hom.:

7761

Bravo

AF:

0.364

Asia WGS

AF:

0.540

AC:

1880

AN:

3478

EpiCase

AF:

0.246

EpiControl

AF:

0.238

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2021	The p.Arg569Arg variant in PKLP is classified as benign because it has been identified in 70% (13958/19872) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1, BP7. -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
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

-0.43

CADD

Benign

8.9

DANN

Benign

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over