NM_000298.6:c.*14C>T

Variant names:

• chr1-155290558-G-A
• rs8177994
• NM_000298.6:c.*14C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000298.6(PKLR):​c.*14C>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 0.000441 in 1,522,114 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: PKLR NM_000298.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.66
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.*14C>T		3_prime_UTR	Exon 11 of 11	NP_000289.1	P30613-1
	PKLR	NM_181871.4		c.*14C>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.*14C>T		3_prime_UTR	Exon 11 of 11	ENSP00000339933.4	P30613-1
	PKLR	ENST00000392414.7	TSL:1	c.*14C>T		3_prime_UTR	Exon 11 of 11	ENSP00000376214.3	P30613-2

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 152090 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00691

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000656 AC: 164 AN: 249940 AF XY: 0.000510

Gnomad AFR exome AF: 0.00779

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000492

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000272 AC: 373 AN: 1369906 Hom.: 1 Cov.: 22 AF XY: 0.000245 AC XY: 168 AN XY: 686638

African (AFR) AF: 0.00733 AC: 229 AN: 31228

American (AMR) AF: 0.000584 AC: 26 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25582

East Asian (EAS) AF: 0.000641 AC: 25 AN: 39024

South Asian (SAS) AF: 0.000131 AC: 11 AN: 84260

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53088

Middle Eastern (MID) AF: 0.000357 AC: 2 AN: 5610

European-Non Finnish (NFE) AF: 0.0000525 AC: 54 AN: 1029338

Other (OTH) AF: 0.000437 AC: 25 AN: 57234

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152208 Hom.: 2 Cov.: 31 AF XY: 0.00195 AC XY: 145 AN XY: 74418

African (AFR) AF: 0.00694 AC: 288 AN: 41514

American (AMR) AF: 0.000458 AC: 7 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.00221

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pyruvate kinase deficiency of red cells (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.50
DANN	Benign	0.85
PhyloP100		-4.7
Mutation Taster		=100/0	polymorphism

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: rs8177994; hg19: chr1-155260349;