rs3762272

Positions:

• chr1-155291986-C-T

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.1437-49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 1,563,796 control chromosomes in the GnomAD database, including 15,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (1605 hom., cov: 31)
  • Exomes 𝑓: 0.055 (14296 hom.)
• Consequence: PKLR NM_000298.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.700

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=-0.82).
• BP6: Variant 1-155291986-C-T is Benign according to our data. Variant chr1-155291986-C-T is described in ClinVar as [Benign]. Clinvar id is 1252339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155291986-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKLR	NM_000298.6	c.1437-49G>A		intron_variant		ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.1437-49G>A		intron_variant		1	NM_000298.6	ENSP00000339933.4
PKLR	ENST00000392414.7	c.1344-49G>A		intron_variant		1		ENSP00000376214.3

Frequencies

GnomAD3 genomes AF: 0.0592 AC: 9006 AN: 152006 Hom.: 1598 Cov.: 31

Gnomad AFR AF: 0.00901

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.0627

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0584

GnomAD3 exomes AF: 0.131 AC: 31789 AN: 242168 Hom.: 6505 AF XY: 0.124 AC XY: 16337 AN XY: 131696

Gnomad AFR exome AF: 0.00882

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.681

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.0632

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0809

GnomAD4 exome AF: 0.0554 AC: 78154 AN: 1411672 Hom.: 14296 Cov.: 23 AF XY: 0.0581 AC XY: 40987 AN XY: 704972

Gnomad4 AFR exome AF: 0.00774

Gnomad4 AMR exome AF: 0.273

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.708

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.0573

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0670

GnomAD4 genome AF: 0.0592 AC: 9013 AN: 152124 Hom.: 1605 Cov.: 31 AF XY: 0.0686 AC XY: 5103 AN XY: 74372

Gnomad4 AFR AF: 0.00901

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.0395

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.0627

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0555

Alfa AF: 0.0258 Hom.: 90

Bravo AF: 0.0697

Asia WGS AF: 0.385 AC: 1334 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.66

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: rs3762272; hg19: chr1-155261777;