rs932972

Variant names:

• chr1-155290305-G-A
• rs932972
• NM_000298.6:c.*267C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-155290305-G-A
• chr1-155290305-G-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.*267C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 517,590 control chromosomes in the GnomAD database, including 30,088 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10488 hom., cov: 31)
  • Exomes 𝑓: 0.30 (19600 hom.)
• Consequence: PKLR NM_000298.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.578
• Publications: 30 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: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, ClinGen
• 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=-0.84).
• BP6: Variant 1-155290305-G-A is Benign according to our data. Variant chr1-155290305-G-A is described in ClinVar as Benign. ClinVar VariationId is 292802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000298.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	NM_000298.6	MANE Select	c.*267C>T		3_prime_UTR	Exon 11 of 11	NP_000289.1	P30613-1
	PKLR	NM_181871.4		c.*267C>T		3_prime_UTR	Exon 11 of 11	NP_870986.1	P30613-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.*267C>T		3_prime_UTR	Exon 11 of 11	ENSP00000339933.4	P30613-1
	PKLR	ENST00000392414.7	TSL:1	c.*267C>T		3_prime_UTR	Exon 11 of 11	ENSP00000376214.3	P30613-2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53375 AN: 151902 Hom.: 10453 Cov.: 31

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: 0.340

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.335

GnomAD4 exome AF: 0.299 AC: 109331 AN: 365570 Hom.: 19600 Cov.: 0 AF XY: 0.298 AC XY: 56945 AN XY: 191342

African (AFR) AF: 0.491 AC: 5178 AN: 10542

American (AMR) AF: 0.360 AC: 5662 AN: 15712

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 2447 AN: 11596

East Asian (EAS) AF: 0.715 AC: 17019 AN: 23800

South Asian (SAS) AF: 0.309 AC: 12528 AN: 40502

European-Finnish (FIN) AF: 0.283 AC: 6380 AN: 22512

Middle Eastern (MID) AF: 0.187 AC: 305 AN: 1634

European-Non Finnish (NFE) AF: 0.246 AC: 53589 AN: 217970

Other (OTH) AF: 0.292 AC: 6223 AN: 21302

GnomAD4 genome AF: 0.352 AC: 53461 AN: 152020 Hom.: 10488 Cov.: 31 AF XY: 0.354 AC XY: 26344 AN XY: 74316

African (AFR) AF: 0.491 AC: 20348 AN: 41444

American (AMR) AF: 0.334 AC: 5100 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3466

East Asian (EAS) AF: 0.701 AC: 3620 AN: 5162

South Asian (SAS) AF: 0.340 AC: 1639 AN: 4824

European-Finnish (FIN) AF: 0.319 AC: 3374 AN: 10572

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

European-Non Finnish (NFE) AF: 0.262 AC: 17782 AN: 67970

Other (OTH) AF: 0.331 AC: 698 AN: 2110

Alfa AF: 0.285 Hom.: 8558

Bravo AF: 0.364

Asia WGS AF: 0.540 AC: 1877 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Pyruvate kinase deficiency of red cells (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.5
DANN	Benign	0.60
PhyloP100		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs932972; hg19: chr1-155260096;