rs41264939

Variant names:

• chr1-155289679-A-C
• rs41264939
• NM_020897.3:c.*1216A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_020897.3(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 NM_020897.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.246
• Publications: 3 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: Orphanet, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• pyruvate kinase hyperactivity

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN3	NM_020897.3	MANE Select	c.*1216A>C		3_prime_UTR	Exon 8 of 8	NP_065948.1	Q9P1Z3
	PKLR	NM_000298.6	MANE Select	c.*893T>G		3_prime_UTR	Exon 11 of 11	NP_000289.1	P30613-1
	PKLR	NM_181871.4		c.*893T>G		3_prime_UTR	Exon 11 of 11	NP_870986.1	P30613-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN3	ENST00000368358.4	TSL:1 MANE Select	c.*1216A>C		3_prime_UTR	Exon 8 of 8	ENSP00000357342.3	Q9P1Z3
	PKLR	ENST00000342741.6	TSL:1 MANE Select	c.*893T>G		3_prime_UTR	Exon 11 of 11	ENSP00000339933.4	P30613-1
	HCN3	ENST00000967752.1		c.*1216A>C		3_prime_UTR	Exon 8 of 8	ENSP00000637811.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00714 AC: 1 AN: 140

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0568 AC: 5 AN: 88

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.00123 AC: 51 AN: 41458

American (AMR) AF: 0.00183 AC: 28 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.0291 AC: 308 AN: 10572

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

European-Non Finnish (NFE) AF: 0.00755 AC: 513 AN: 67970

Other (OTH) AF: 0.00476 AC: 10 AN: 2102

Alfa AF: 0.00582 Hom.: 0

Bravo AF: 0.00375

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	-0.72
CADD	Benign	5.6
DANN	Benign	0.86
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism

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: rs41264939; hg19: chr1-155259470;