rs556807161
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014425.5(INVS):c.2380C>T(p.Arg794Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R794H) has been classified as Uncertain significance.
Frequency
Consequence
NM_014425.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INVS | NM_014425.5 | c.2380C>T | p.Arg794Cys | missense_variant | 14/17 | ENST00000262457.7 | |
INVS | NM_001318381.2 | c.2092C>T | p.Arg698Cys | missense_variant | 15/18 | ||
INVS | NM_001318382.2 | c.1402C>T | p.Arg468Cys | missense_variant | 14/17 | ||
INVS | NR_134606.2 | n.2529C>T | non_coding_transcript_exon_variant | 14/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INVS | ENST00000262457.7 | c.2380C>T | p.Arg794Cys | missense_variant | 14/17 | 1 | NM_014425.5 | A2 | |
INVS | ENST00000262456.6 | c.2179+201C>T | intron_variant | 5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249122Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134870
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727242
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74324
ClinVar
Submissions by phenotype
Nephronophthisis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2021 | This sequence change replaces arginine with cysteine at codon 794 of the INVS protein (p.Arg794Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs556807161, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with INVS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Infantile nephronophthisis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | INVS NM_014425.4 exon 14 p.Arg794Cys (c.2380C>T): This variant has not been reported in the literature but is present in 1/109414 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs556807161). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at