1-155289679-A-C

Position:

• chr1-155289679-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000368358.4(HCN3):​c.*1216A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 152,270 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 31)
  • Exomes 𝑓: 0.024 (0 hom.)
• Consequence: HCN3 ENST00000368358.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.246

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0244 (6/246) while in subpopulation NFE AF= 0.0568 (5/88). AF 95% confidence interval is 0.0224. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKLR	NM_000298.6	c.*893T>G		3_prime_UTR_variant	11/11	ENST00000342741.6	NP_000289.1
HCN3	NM_020897.3	c.*1216A>C		3_prime_UTR_variant	8/8	ENST00000368358.4	NP_065948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKLR	ENST00000342741.6	c.*893T>G		3_prime_UTR_variant	11/11	1	NM_000298.6	ENSP00000339933	P3
HCN3	ENST00000368358.4	c.*1216A>C		3_prime_UTR_variant	8/8	1	NM_020897.3	ENSP00000357342	P1
HCN3	ENST00000496230.5	n.3077A>C		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 911 AN: 151906 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00755

Gnomad OTH AF: 0.00481

GnomAD4 exome AF: 0.0244 AC: 6 AN: 246 Hom.: 0 Cov.: 0 AF XY: 0.0338 AC XY: 5 AN XY: 148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00714

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0568

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00599 AC: 911 AN: 152024 Hom.: 6 Cov.: 31 AF XY: 0.00672 AC XY: 499 AN XY: 74310

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0291

Gnomad4 NFE AF: 0.00755

Gnomad4 OTH AF: 0.00476

Alfa AF: 0.00582 Hom.: 0

Bravo AF: 0.00375

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate kinase deficiency of red cells Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.6
DANN	Benign	0.86

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: rs41264939; hg19: chr1-155259470;