rs397515340

chr6-43670917-GAGA-Gchr6-43670917-GAGA-GAGAAGA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_152732.5(RSPH9):c.804_806del(p.Lys268del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000979 in 1,614,188 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: RSPH9 NM_152732.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.66

Genes affected

RSPH9 (HGNC:21057): (radial spoke head component 9) This gene encodes a protein thought to be a component of the radial spoke head in motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia 12. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jul 2010]

POLR1C (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_152732.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-43670917-GAGA-G is Pathogenic according to our data. Variant chr6-43670917-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 66994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43670917-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH9	NM_152732.5	c.804_806del	p.Lys268del	inframe_deletion	5/5	ENST00000372163.5
RSPH9	NM_001193341.2	c.856_858del	p.Glu286del	inframe_deletion	6/6
POLR1C	NM_001318876.2	c.945+141651_945+141653del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH9	ENST00000372163.5	c.804_806del	p.Lys268del	inframe_deletion	5/5	1	NM_152732.5	P1
RSPH9	ENST00000372165.8	c.856_858del	p.Glu286del	inframe_deletion	6/6	2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251438 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135906

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461866 Hom.: 1 AF XY: 0.000103 AC XY: 75 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000226 Hom.: 0

Bravo AF: 0.0000604

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 12 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 28, 2020	This variant was reported in the homozygous state in multiple individuals presenting with pulmonary disease. A functional study has demonstrated that this variant causes immotile or abnormally beating cilia. RSPH9 c.804_806delGAA (rs909605187) is rare (<0.1%) in a large population dataset (gnomAD: 14/282846 total alleles; 0.005%; no homozygotes). This variant has been reported in ClinVar. RSPH9 c.804_806delGAA was found to segregate with disease in a large family. We consider this variant to be pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

This variant, c.804_806del, results in the deletion of 1 amino acid(s) of the RSPH9 protein (p.Lys268del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs748432026, gnomAD 0.01%). This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 19200523, 22384920, 23993197; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.801_803delGAA. ClinVar contains an entry for this variant (Variation ID: 66994). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects RSPH9 function (PMID: 19200523). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2022

Published functional studies demonstrate a damaging effect consistent with a hypomorphic allele (Castleman et al., 2009); In-frame deletion of 1 amino acid in a non-repeat region.; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31772028, 19200523, 22384920, 23993197, 31130284, 31879361, 31589614, 33726816, 34401452) -

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: rs397515340; hg19: chr6-43638654;