rs146142715
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The ENST00000229554.10(RSPH4A):c.1990C>T(p.Pro664Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,978 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 8 hom. )
Consequence
RSPH4A
ENST00000229554.10 missense
ENST00000229554.10 missense
Scores
1
3
15
Clinical Significance
Conservation
PhyloP100: 0.0220
Genes affected
RSPH4A (HGNC:21558): (radial spoke head component 4A) This gene encodes a protein that appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein. Mutations in this gene cause primary ciliary dyskinesia 1, a disease arising from dysmotility of motile cilia and sperm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.008825988).
BP6
Variant 6-116632280-C-T is Benign according to our data. Variant chr6-116632280-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 355124.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High Homozygotes in GnomAdExome4 at 8 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RSPH4A | NM_001010892.3 | c.1990C>T | p.Pro664Ser | missense_variant | 6/6 | ENST00000229554.10 | NP_001010892.1 | |
LOC124901386 | XR_007059721.1 | n.459+1525G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RSPH4A | ENST00000229554.10 | c.1990C>T | p.Pro664Ser | missense_variant | 6/6 | 1 | NM_001010892.3 | ENSP00000229554 | P1 | |
RSPH4A | ENST00000368581.8 | c.*51C>T | 3_prime_UTR_variant | 5/5 | 1 | ENSP00000357570 | ||||
RSPH4A | ENST00000368580.4 | c.1249C>T | p.Pro417Ser | missense_variant | 5/5 | 5 | ENSP00000357569 |
Frequencies
GnomAD3 genomes AF: 0.00118 AC: 180AN: 152058Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00156 AC: 392AN: 251346Hom.: 3 AF XY: 0.00163 AC XY: 222AN XY: 135836
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GnomAD4 exome AF: 0.00143 AC: 2092AN: 1460802Hom.: 8 Cov.: 31 AF XY: 0.00140 AC XY: 1018AN XY: 726748
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GnomAD4 genome AF: 0.00118 AC: 180AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103AN XY: 74404
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 | clinical testing | Eurofins Ntd Llc (ga) | Oct 06, 2016 | - - |
RSPH4A-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 21, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Primary ciliary dyskinesia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at