chr21-42493049-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_080860.4(RSPH1):c.85G>T(p.Glu29*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

RSPH1
NM_080860.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 3.25

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]

RSPH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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. Fraction of 0.909 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-42493049-C-A is Pathogenic according to our data. Variant chr21-42493049-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 66987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4 link	c.85G>T	p.Glu29*	stop_gained	Exon 2 of 9	ENST00000291536.8	NP_543136.1	Q8WYR4-1
RSPH1	XM_011529786.2 link	c.85G>T	p.Glu29*	stop_gained	Exon 2 of 8		XP_011528088.1
RSPH1	NM_001286506.2 link	c.55-186G>T		intron_variant	Intron 1 of 7		NP_001273435.1	Q8WYR4-2
RSPH1	XM_005261208.3 link	c.67+3071G>T		intron_variant	Intron 1 of 6		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH1	ENST00000291536.8 link	c.85G>T	p.Glu29*	stop_gained	Exon 2 of 9	1	NM_080860.4	ENSP00000291536.3	Q8WYR4-1
RSPH1	ENST00000398352.3 link	c.55-186G>T		intron_variant	Intron 1 of 7	5		ENSP00000381395.3	Q8WYR4-2
RSPH1	ENST00000493019.1 link	n.145G>T		non_coding_transcript_exon_variant	Exon 2 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000258

AC:

AN:

251460

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000352

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000187

AC:

273

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000151

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 24

Pathogenic:5

May 07, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1, PM3 very strong -

Sep 05, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This RSPH1 nonsense variant has been identified in multiple individuals with primary ciliary dyskinesia in both the homozygous and compound heterozygous states. This variant (rs138320978) is rare (<0.1%) in a large population dataset (gnomAD: 67/282852 total alleles; 0.02369%; no homozygotes) and has been reported in ClinVar (Variation ID: 66987). This nonsense variant results in a premature stop codon in exon 2 likely leading to nonsense-mediated decay and lack of protein production. We consider this variant to be pathogenic. -

Jun 18, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia

Pathogenic:2

Jul 27, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu29X (NM_080860.2 c.85G>T) variant in RSPH1 has been previously reported in at least 5 homozygous and 5 compound heterozygous individuals with primary ciliary dyskinesia (Kott 2013, Marshall 2015, Onoufriadis 2014, Knowles 2014). T his variant has been identified in 40/126,700 of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs1383 20978). Although this variant has been seen in the general population, its frequ ency is low enough to be consistent with a recessive carrier frequency. This non sense variant leads to a premature termination codon at position 29, which is pr edicted to lead to a truncated or absent protein. Biallelic loss of function of the RSPH1 gene has been associated with primary ciliary dyskinesia. In summary, this variant meets criteria to be classified as pathogenic for primary ciliary d yskinesia in an autosomal recessive manner based upon its biallelic occurrence i n individuals with this disease and the predicted impact on the protein. ACMG/AM P criteria applied: PVS1, PM3 (upgraded to Strong based on multiple occurrences) . -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu29*) in the RSPH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RSPH1 are known to be pathogenic (PMID: 23993197). This variant is present in population databases (rs138320978, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 23993197, 24518672, 24568568, 26139845). ClinVar contains an entry for this variant (Variation ID: 66987). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Nov 08, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3_strong, PS4, PVS1 -

Kartagener syndrome

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

Vest4

0.26

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over