chr6-116616695-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_001010892.3(RSPH4A):​c.72G>A​(p.Trp24*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RSPH4A
NM_001010892.3 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.30
Variant links:
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 Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-116616695-G-A is Pathogenic according to our data. Variant chr6-116616695-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2113289.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RSPH4ANM_001010892.3 linkc.72G>A p.Trp24* stop_gained 1/6 ENST00000229554.10 NP_001010892.1 Q5TD94-1B3KTA9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RSPH4AENST00000229554.10 linkc.72G>A p.Trp24* stop_gained 1/61 NM_001010892.3 ENSP00000229554.5 Q5TD94-1
RSPH4AENST00000368581.8 linkc.72G>A p.Trp24* stop_gained 1/51 ENSP00000357570.4 Q5TD94-3
RSPH4AENST00000368580.4 linkc.72G>A p.Trp24* stop_gained 1/55 ENSP00000357569.4 Q5TD94-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 11, 2023For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with RSPH4A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp24*) in the RSPH4A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RSPH4A are known to be pathogenic (PMID: 19200523). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Benign
0.65
D
Vest4
0.13
GERP RS
4.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1775508204; hg19: chr6-116937858; API