rs200382776

chr21-42477286-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_080860.4(RSPH1):c.727+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000578 in 1,453,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000058 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RSPH1 NM_080860.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9967
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.708

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 21-42477286-C-T is Pathogenic according to our data. Variant chr21-42477286-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH1	NM_080860.4	c.727+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000291536.8
RSPH1	NM_001286506.2	c.613+5G>A		splice_donor_5th_base_variant, intron_variant
RSPH1	XM_005261208.3	c.520+5G>A		splice_donor_5th_base_variant, intron_variant
RSPH1	XM_011529786.2	c.655+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8	c.727+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_080860.4	P1
RSPH1	ENST00000398352.3	c.613+5G>A		splice_donor_5th_base_variant, intron_variant		5
RSPH1	ENST00000493019.1	n.2345+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9 AN: 145832 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.0000496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000654

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000464

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000264 AC: 66 AN: 249612 Hom.: 0 AF XY: 0.000237 AC XY: 32 AN XY: 135052

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.000426

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000578 AC: 84 AN: 1453100 Hom.: 0 Cov.: 34 AF XY: 0.0000498 AC XY: 36 AN XY: 722838

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000199

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000617 AC: 9 AN: 145940 Hom.: 0 Cov.: 33 AF XY: 0.0000842 AC XY: 6 AN XY: 71220

Gnomad4 AFR AF: 0.0000494

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.000655

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000464

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000137 Hom.: 0

EpiCase AF: 0.0000549

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 24 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 22, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -

Primary ciliary dyskinesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2023

This sequence change falls in intron 7 of the RSPH1 gene. It does not directly change the encoded amino acid sequence of the RSPH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23993197). ClinVar contains an entry for this variant (Variation ID: 208999). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in inclusion of 2 nt of intronic sequence and introduces a premature termination codon (PMID: 23993197). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Mar 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	18
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs200382776; hg19: chr21-43897396;