rs3762272

Variant names:

• chr1-155291986-C-T
• rs3762272
• NM_000298.6:c.1437-49G>A

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.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
• Publications: 12 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=-0.82).
• BP6: Variant 1-155291986-C-T is Benign according to our data. Variant chr1-155291986-C-T is described in ClinVar as Benign. ClinVar VariationId is 1252339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKLR	NM_000298.6	c.1437-49G>A		intron_variant	Intron 9 of 10	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.1437-49G>A		intron_variant	Intron 9 of 10	1	NM_000298.6	ENSP00000339933.4
PKLR	ENST00000392414.7	c.1344-49G>A		intron_variant	Intron 9 of 10	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

GnomAD2 exomes AF: 0.131 AC: 31789 AN: 242168 AF XY: 0.124

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 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

African (AFR) AF: 0.00774 AC: 251 AN: 32418

American (AMR) AF: 0.273 AC: 12081 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 1048 AN: 25844

East Asian (EAS) AF: 0.708 AC: 27887 AN: 39400

South Asian (SAS) AF: 0.192 AC: 16340 AN: 85084

European-Finnish (FIN) AF: 0.0573 AC: 3031 AN: 52906

Middle Eastern (MID) AF: 0.0154 AC: 63 AN: 4098

European-Non Finnish (NFE) AF: 0.0127 AC: 13527 AN: 1069164

Other (OTH) AF: 0.0670 AC: 3926 AN: 58576

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

African (AFR) AF: 0.00901 AC: 374 AN: 41504

American (AMR) AF: 0.145 AC: 2222 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3470

East Asian (EAS) AF: 0.682 AC: 3521 AN: 5160

South Asian (SAS) AF: 0.213 AC: 1028 AN: 4818

European-Finnish (FIN) AF: 0.0627 AC: 665 AN: 10600

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0135 AC: 919 AN: 67984

Other (OTH) AF: 0.0555 AC: 117 AN: 2110

Alfa AF: 0.0270 Hom.: 223

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

-

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	-0.82
CADD	Benign	4.1
DANN	Benign	0.66
PhyloP100		-0.70
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: rs3762272; hg19: chr1-155261777;