rs587777059

Positions:

• chr21-42485759-ATACT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_080860.4(RSPH1):​c.407_410del​(p.Lys136MetfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RSPH1 NM_080860.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 8.12

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-42485759-ATACT-A is Pathogenic according to our data. Variant chr21-42485759-ATACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66989.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH1	NM_080860.4	c.407_410del	p.Lys136MetfsTer6	frameshift_variant	5/9	ENST00000291536.8
RSPH1	NM_001286506.2	c.293_296del	p.Lys98MetfsTer6	frameshift_variant	4/8
RSPH1	XM_005261208.3	c.200_203del	p.Lys67MetfsTer6	frameshift_variant	3/7
RSPH1	XM_011529786.2	c.407_410del	p.Lys136MetfsTer6	frameshift_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8	c.407_410del	p.Lys136MetfsTer6	frameshift_variant	5/9	1	NM_080860.4	P1
RSPH1	ENST00000398352.3	c.293_296del	p.Lys98MetfsTer6	frameshift_variant	4/8	5
RSPH1	ENST00000493019.1	n.1033_1036del		non_coding_transcript_exon_variant	4/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461884 Hom.: 0 AF XY: 0.0000138 AC XY: 10 AN XY: 727246

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: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 24 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 23, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 05, 2013	- -

Kartagener syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587777059; hg19: chr21-43905869;