rs8847

Variant names:

• chr1-155289532-C-T
• rs8847
• NM_020897.3:c.*1069C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020897.3(HCN3):​c.*1069C>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 0.352 in 152,134 control chromosomes in the GnomAD database, including 10,493 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (10479 hom., cov: 31)
  • Exomes 𝑓: 0.29 (14 hom.)
• Consequence: HCN3 NM_020897.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.536
• Publications: 14 publications found

Genes affected

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]

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCN3	NM_020897.3	c.*1069C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000368358.4	NP_065948.1
PKLR	NM_000298.6	c.*1040G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000342741.6	NP_000289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCN3	ENST00000368358.4	c.*1069C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_020897.3	ENSP00000357342.3
PKLR	ENST00000342741.6	c.*1040G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_000298.6	ENSP00000339933.4
HCN3	ENST00000496230.5	n.2930C>T		non_coding_transcript_exon_variant	Exon 8 of 8	2
HCN3	ENST00000492035.1	n.*14C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53331 AN: 151782 Hom.: 10444 Cov.: 31

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.286 AC: 67 AN: 234 Hom.: 14 Cov.: 0 AF XY: 0.316 AC XY: 50 AN XY: 158

African (AFR) AF: 0.333 AC: 2 AN: 6

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.262 AC: 22 AN: 84

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.273 AC: 6 AN: 22

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 24 AN: 96

Other (OTH) AF: 0.611 AC: 11 AN: 18

GnomAD4 genome AF: 0.352 AC: 53417 AN: 151900 Hom.: 10479 Cov.: 31 AF XY: 0.354 AC XY: 26289 AN XY: 74224

African (AFR) AF: 0.491 AC: 20341 AN: 41386

American (AMR) AF: 0.334 AC: 5103 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3470

East Asian (EAS) AF: 0.702 AC: 3609 AN: 5142

South Asian (SAS) AF: 0.340 AC: 1636 AN: 4806

European-Finnish (FIN) AF: 0.318 AC: 3352 AN: 10538

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.262 AC: 17780 AN: 67964

Other (OTH) AF: 0.330 AC: 696 AN: 2106

Alfa AF: 0.291 Hom.: 2454

Bravo AF: 0.364

Asia WGS AF: 0.540 AC: 1878 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate kinase deficiency of red cells Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.91
DANN	Benign	0.50
PhyloP100		-0.54
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: rs8847; hg19: chr1-155259323;