1-155290073-C-T

Variant names:

• chr1-155290073-C-T
• rs777573500
• NM_000298.6:c.*499G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000298.6(PKLR):​c.*499G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 171,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: PKLR NM_000298.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.55
• Publications: 1 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]

HCN3 (HGNC:19183): (hyperpolarization activated cyclic nucleotide gated potassium channel 3) This gene encodes a multi-pass membrane protein that functions as a voltage gated cation channel. The encoded protein is a member of a family of closely related cyclic adenosine monophosphate-binding channel proteins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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.*499G>A		3_prime_UTR	Exon 11 of 11	NP_000289.1	P30613-1
	PKLR	NM_181871.4		c.*499G>A		3_prime_UTR	Exon 11 of 11	NP_870986.1	P30613-2
	HCN3	NM_020897.3	MANE Select	c.*1610C>T		downstream_gene	N/A	NP_065948.1	Q9P1Z3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.*499G>A		3_prime_UTR	Exon 11 of 11	ENSP00000339933.4	P30613-1
	PKLR	ENST00000392414.7	TSL:1	c.*499G>A		3_prime_UTR	Exon 11 of 11	ENSP00000376214.3	P30613-2
	HCN3	ENST00000368358.4	TSL:1 MANE Select	c.*1610C>T		downstream_gene	N/A	ENSP00000357342.3	Q9P1Z3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000364 AC: 7 AN: 19226 Hom.: 0 Cov.: 0 AF XY: 0.000306 AC XY: 3 AN XY: 9796

African (AFR) AF: 0.00 AC: 0 AN: 600

American (AMR) AF: 0.00 AC: 0 AN: 2418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 388

East Asian (EAS) AF: 0.00 AC: 0 AN: 1204

South Asian (SAS) AF: 0.00 AC: 0 AN: 1772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 66

European-Non Finnish (NFE) AF: 0.000619 AC: 7 AN: 11312

Other (OTH) AF: 0.00 AC: 0 AN: 998

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152234 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74420

African (AFR) AF: 0.00 AC: 0 AN: 41526

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000196

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	-0.89
CADD	Benign	0.10
DANN	Benign	0.59
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777573500; hg19: chr1-155259864;