21-42475897-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_080860.4(RSPH1):​c.877+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 28)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RSPH1
NM_080860.4 splice_donor, intron

Scores

1
6
Splicing: ADA: 0.9997
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.777
Variant links:
Genes affected
RSPH1 (HGNC:12371): (radial spoke head component 1) This gene encodes a male meiotic metaphase chromosome-associated acidic protein. This gene is expressed in tissues with motile cilia or flagella, including the trachea, lungs, airway brushings, and testes. Mutations in this gene result in primary ciliary dyskinesia-24. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.16129032 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RSPH1NM_080860.4 linkc.877+1G>A splice_donor_variant, intron_variant Intron 8 of 8 ENST00000291536.8 NP_543136.1 Q8WYR4-1
RSPH1NM_001286506.2 linkc.763+1G>A splice_donor_variant, intron_variant Intron 7 of 7 NP_001273435.1 Q8WYR4-2
RSPH1XM_011529786.2 linkc.805+1G>A splice_donor_variant, intron_variant Intron 7 of 7 XP_011528088.1
RSPH1XM_005261208.3 linkc.670+1G>A splice_donor_variant, intron_variant Intron 6 of 6 XP_005261265.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RSPH1ENST00000291536.8 linkc.877+1G>A splice_donor_variant, intron_variant Intron 8 of 8 1 NM_080860.4 ENSP00000291536.3 Q8WYR4-1
RSPH1ENST00000398352.3 linkc.763+1G>A splice_donor_variant, intron_variant Intron 7 of 7 5 ENSP00000381395.3 Q8WYR4-2
RSPH1ENST00000493019.1 linkn.2495+1G>A splice_donor_variant, intron_variant Intron 7 of 7 2

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461804
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
28

ClinVar

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

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1
Nov 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects a donor splice site in intron 8 of the RSPH1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RSPH1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.40
CADD
Pathogenic
32
DANN
Benign
0.77
Eigen
Uncertain
0.43
Eigen_PC
Benign
0.15
FATHMM_MKL
Benign
0.23
N
GERP RS
2.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.82
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.74
Position offset: -4
DS_DL_spliceai
0.99
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-43896007; API