chr6-116617207-C-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001010892.3(RSPH4A):āc.584C>Gā(p.Pro195Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,614,150 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). Synonymous variant affecting the same amino acid position (i.e. P195P) has been classified as Likely benign.
Frequency
Consequence
NM_001010892.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RSPH4A | ENST00000229554.10 | c.584C>G | p.Pro195Arg | missense_variant | Exon 1 of 6 | 1 | NM_001010892.3 | ENSP00000229554.5 | ||
RSPH4A | ENST00000368581.8 | c.584C>G | p.Pro195Arg | missense_variant | Exon 1 of 5 | 1 | ENSP00000357570.4 | |||
RSPH4A | ENST00000368580.4 | c.584C>G | p.Pro195Arg | missense_variant | Exon 1 of 5 | 5 | ENSP00000357569.4 |
Frequencies
GnomAD3 genomes AF: 0.000401 AC: 61AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000492 AC: 123AN: 250078Hom.: 0 AF XY: 0.000502 AC XY: 68AN XY: 135524
GnomAD4 exome AF: 0.000579 AC: 846AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.000562 AC XY: 409AN XY: 727236
GnomAD4 genome AF: 0.000401 AC: 61AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74468
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:2Benign:1
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This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 195 of the RSPH4A protein (p.Pro195Arg). This variant is present in population databases (rs141226759, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RSPH4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 165058). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The Pro195Arg varia nt in RSPH4A has not been previously reported in individuals with pulmonary dise ase, but has been identified in 0.093% (8/8600) of European American chromosomes and 0.045% (2/4406) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs141226759). Computational prediction tools and conservation analysis suggest that the Pro195Arg variant m ay not impact the protein, though this information is not predictive enough to r ule out pathogenicity. In summary, while the clinical significance of the Pro195 Arg variant is uncertain, these data suggest that it is more likely to be benign . -
Primary ciliary dyskinesia 11 Uncertain:1
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
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at