rs998387579
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_005477.3(HCN4):c.1448G>A(p.Arg483Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R483W) has been classified as Uncertain significance.
Frequency
Consequence
NM_005477.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HCN4 | NM_005477.3 | c.1448G>A | p.Arg483Gln | missense_variant | 4/8 | ENST00000261917.4 | |
HCN4 | XM_011521148.3 | c.230G>A | p.Arg77Gln | missense_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HCN4 | ENST00000261917.4 | c.1448G>A | p.Arg483Gln | missense_variant | 4/8 | 1 | NM_005477.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251328Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135866
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727212
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152220Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74372
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 02, 2022 | The p.R483Q variant (also known as c.1448G>A), located in coding exon 4 of the HCN4 gene, results from a G to A substitution at nucleotide position 1448. The arginine at codon 483 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Brugada syndrome 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at