rs1064792947

Variant names:

• chr21-42482619-ACATGCTCCGCAACTTAC-A
• rs1064792947
• NM_080860.4:c.573+1_573+17delGTAAGTTGCGGAGCATG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_080860.4(RSPH1):​c.573+1_573+17delGTAAGTTGCGGAGCATG variant causes a splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RSPH1 NM_080860.4 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.88
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 24

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.077419356 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of -6, new splice context is: atgGTgaat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 21-42482619-ACATGCTCCGCAACTTAC-A is Pathogenic according to our data. Variant chr21-42482619-ACATGCTCCGCAACTTAC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 408130.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.573+1_573+17delGTAAGTTGCGGAGCATG		splice_donor_variant, splice_region_variant, intron_variant	Intron 6 of 8	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.459+1_459+17delGTAAGTTGCGGAGCATG		splice_donor_variant, splice_region_variant, intron_variant	Intron 5 of 7		NP_001273435.1
RSPH1	XM_011529786.2	c.501+3033_501+3049delGTAAGTTGCGGAGCATG		intron_variant	Intron 5 of 7		XP_011528088.1
RSPH1	XM_005261208.3	c.366+1_366+17delGTAAGTTGCGGAGCATG		splice_donor_variant, splice_region_variant, intron_variant	Intron 4 of 6		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.573+1_573+17delGTAAGTTGCGGAGCATG		splice_donor_variant, splice_region_variant, intron_variant	Intron 6 of 8	1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.459+1_459+17delGTAAGTTGCGGAGCATG		splice_donor_variant, splice_region_variant, intron_variant	Intron 5 of 7	5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.2191+1_2191+17delGTAAGTTGCGGAGCATG		splice_donor_variant, splice_region_variant, intron_variant	Intron 5 of 7	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Sep 22, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with a RSPH1-related disease. For these reasons, this variant has been classified as Pathogenic. This sequence change deletes 17 nucleotides from intron 6 of the RSPH1 mRNA (c.573+1_573+17del). It affects a donor splice site as well as conserved nucleotides near the donor splice site. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant occurs with a pathogenic variant (c.275-2A>C) in RSPH1 in an individual with clinical findings consistent with primary ciliary dyskinesia (Invitae). While it is unknown if these two variants are on the same or opposite chromosomes, this observation suggests the c.573+1_573+17del substitution may contribute to the cause of disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1064792947; hg19: chr21-43902729;