rs8847

Positions:

• chr1-155289532-C-T

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKLR	NM_000298.6	c.*1040G>A		3_prime_UTR_variant	11/11	ENST00000342741.6
HCN3	NM_020897.3	c.*1069C>T		3_prime_UTR_variant	8/8	ENST00000368358.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKLR	ENST00000342741.6	c.*1040G>A		3_prime_UTR_variant	11/11	1	NM_000298.6	P3
HCN3	ENST00000368358.4	c.*1069C>T		3_prime_UTR_variant	8/8	1	NM_020897.3	P1
HCN3	ENST00000496230.5	n.2930C>T		non_coding_transcript_exon_variant	8/8	2
HCN3	ENST00000492035.1			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

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.262

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.611

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

Gnomad4 AFR AF: 0.491

Gnomad4 AMR AF: 0.334

Gnomad4 ASJ AF: 0.211

Gnomad4 EAS AF: 0.702

Gnomad4 SAS AF: 0.340

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.330

Alfa AF: 0.289 Hom.: 1408

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.91
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs8847; hg19: chr1-155259323;