rs3020781

Variant names:

• chr1-155299985-A-G
• rs3020781
• NM_000298.6:c.283+113T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-155299985-A-G
• chr1-155299985-A-T

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.283+113T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 1,162,072 control chromosomes in the GnomAD database, including 65,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13326 hom., cov: 31)
  • Exomes 𝑓: 0.30 (51873 hom.)
• Consequence: PKLR NM_000298.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.518
• Publications: 28 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=-1.0).
• BP6: Variant 1-155299985-A-G is Benign according to our data. Variant chr1-155299985-A-G is described in ClinVar as [Benign]. Clinvar id is 1237051.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.283+113T>C		intron_variant	Intron 2 of 10	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.283+113T>C		intron_variant	Intron 2 of 10	1	NM_000298.6	ENSP00000339933.4
PKLR	ENST00000392414.7	c.190+113T>C		intron_variant	Intron 2 of 10	1		ENSP00000376214.3
PKLR	ENST00000434082.3	c.91+113T>C		intron_variant	Intron 2 of 4	5		ENSP00000398037.3

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58665 AN: 151954 Hom.: 13282 Cov.: 31

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.359

GnomAD4 exome AF: 0.302 AC: 304565 AN: 1010000 Hom.: 51873 AF XY: 0.299 AC XY: 153134 AN XY: 512692

African (AFR) AF: 0.616 AC: 14937 AN: 24258

American (AMR) AF: 0.413 AC: 16159 AN: 39170

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 4898 AN: 21100

East Asian (EAS) AF: 0.726 AC: 26922 AN: 37058

South Asian (SAS) AF: 0.328 AC: 23460 AN: 71422

European-Finnish (FIN) AF: 0.305 AC: 15033 AN: 49272

Middle Eastern (MID) AF: 0.206 AC: 983 AN: 4770

European-Non Finnish (NFE) AF: 0.262 AC: 188119 AN: 717990

Other (OTH) AF: 0.313 AC: 14054 AN: 44960

GnomAD4 genome AF: 0.386 AC: 58758 AN: 152072 Hom.: 13326 Cov.: 31 AF XY: 0.387 AC XY: 28800 AN XY: 74338

African (AFR) AF: 0.608 AC: 25211 AN: 41468

American (AMR) AF: 0.343 AC: 5246 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 769 AN: 3466

East Asian (EAS) AF: 0.702 AC: 3636 AN: 5180

South Asian (SAS) AF: 0.340 AC: 1641 AN: 4824

European-Finnish (FIN) AF: 0.320 AC: 3382 AN: 10568

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17953 AN: 67970

Other (OTH) AF: 0.355 AC: 749 AN: 2112

Alfa AF: 0.304 Hom.: 7144

Bravo AF: 0.403

Asia WGS AF: 0.546 AC: 1899 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.1
DANN	Benign	0.63
PhyloP100		0.52
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: rs3020781; hg19: chr1-155269776; COSMIC: COSV61362210;