chr1-155300271-C-T

Variant names:

• chr1-155300271-C-T
• rs118204087
• NM_000298.6:c.110G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000298.6(PKLR):​c.110G>A​(p.Gly37Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Affects (no stars). Synonymous variant affecting the same amino acid position (i.e. G37G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PKLR NM_000298.6 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 1.29
• Publications: 8 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.98056 (below the threshold of 3.09). Trascript score misZ: 1.5963 (below the threshold of 3.09). GenCC associations: The gene is linked to pyruvate kinase deficiency of red cells, pyruvate kinase hyperactivity.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	NM_000298.6	MANE Select	c.110G>A	p.Gly37Glu	missense	Exon 2 of 11	NP_000289.1
	PKLR	NM_181871.4		c.17G>A	p.Gly6Glu	missense	Exon 2 of 11	NP_870986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.110G>A	p.Gly37Glu	missense	Exon 2 of 11	ENSP00000339933.4
	PKLR	ENST00000392414.7	TSL:1	c.17G>A	p.Gly6Glu	missense	Exon 2 of 11	ENSP00000376214.3
	PKLR	ENST00000434082.3	TSL:5	c.-21-62G>A		intron	N/A	ENSP00000398037.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439044 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 714310

African (AFR) AF: 0.00 AC: 0 AN: 32916

American (AMR) AF: 0.00 AC: 0 AN: 40410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 38342

South Asian (SAS) AF: 0.00 AC: 0 AN: 84086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5248

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101190

Other (OTH) AF: 0.00 AC: 0 AN: 59526

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Pyruvate kinase hyperactivity Other:1

Jan 01, 1965

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.16	N
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L
PhyloP100		1.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.22	T
Polyphen		0.92	P
Vest4		0.52
MutPred		0.74		Loss of sheet (P = 0.0315)
MVP		0.98
MPC		1.5
ClinPred		0.78	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.82
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs118204087; hg19: chr1-155270062;