rs8847

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. Variant has been reported in ClinVar as Benign (★★).

• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-155289532-C-T is Benign according to our data. Variant chr1-155289532-C-T is described in ClinVar as Benign. ClinVar VariationId is 292792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020897.3. 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
	HCN3	NM_020897.3	MANE Select	c.*1069C>T		3_prime_UTR	Exon 8 of 8	NP_065948.1
	PKLR	NM_000298.6	MANE Select	c.*1040G>A		3_prime_UTR	Exon 11 of 11	NP_000289.1
	HCN3	NR_073074.2		n.3389C>T		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN3	ENST00000368358.4	TSL:1 MANE Select	c.*1069C>T		3_prime_UTR	Exon 8 of 8	ENSP00000357342.3
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.*1040G>A		3_prime_UTR	Exon 11 of 11	ENSP00000339933.4
	HCN3	ENST00000496230.5	TSL:2	n.2930C>T		non_coding_transcript_exon	Exon 8 of 8

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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;