chr1-155290559-A-G

Variant names:

• chr1-155290559-A-G
• rs1052177
• NM_000298.6:c.*13T>C

Variant summary

Our verdict is Benign. The variant received -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:7
• Conservation: PhyloP100: -0.833
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• pyruvate kinase deficiency of red cells

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• pyruvate kinase hyperactivity

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 255797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PKLR	NM_000298.6	c.*13T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.*13T>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_000298.6	ENSP00000339933.4
PKLR	ENST00000392414.7	c.*13T>C		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000376214.3

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

GnomAD2 exomes AF: 0.335 AC: 83360 AN: 248570 AF XY: 0.325

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 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

African (AFR) AF: 0.489 AC: 15288 AN: 31278

American (AMR) AF: 0.405 AC: 17970 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5616 AN: 25572

East Asian (EAS) AF: 0.724 AC: 28271 AN: 39070

South Asian (SAS) AF: 0.325 AC: 27412 AN: 84314

European-Finnish (FIN) AF: 0.302 AC: 15933 AN: 52726

Middle Eastern (MID) AF: 0.196 AC: 1097 AN: 5600

European-Non Finnish (NFE) AF: 0.251 AC: 258943 AN: 1031602

Other (OTH) AF: 0.298 AC: 17107 AN: 57370

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

African (AFR) AF: 0.492 AC: 20298 AN: 41290

American (AMR) AF: 0.335 AC: 5098 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 731 AN: 3464

East Asian (EAS) AF: 0.702 AC: 3624 AN: 5162

South Asian (SAS) AF: 0.341 AC: 1638 AN: 4802

European-Finnish (FIN) AF: 0.318 AC: 3349 AN: 10522

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17767 AN: 67886

Other (OTH) AF: 0.330 AC: 695 AN: 2104

Alfa AF: 0.266 Hom.: 7120

Bravo AF: 0.364

Asia WGS AF: 0.539 AC: 1876 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 19, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pyruvate kinase deficiency of red cells Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1052177; hg19: chr1-155260350;