Variant 6-43645099-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_152732.5(RSPH9):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000137 in 1,458,614 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: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RSPH9
NM_152732.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.96

Variant links:

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]

RSPH9 links:

POLR1C (HGNC:):

POLR1C links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_152732.5 (RSPH9) was described as [Likely_pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-43645099-A-G is Pathogenic according to our data. Variant chr6-43645099-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1392419.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH9	NM_152732.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/5	ENST00000372163.5	NP_689945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH9	ENST00000372163.5 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/5	1	NM_152732.5	ENSP00000361236	P1	Q9H1X1-1
RSPH9	ENST00000372165.8 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/6	2		ENSP00000361238		Q9H1X1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458614

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725780

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2022

Disruption of the initiator codon has been observed in individuals with primary ciliary dyskinesia (PMID: 23993197, 25789548; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the RSPH9 mRNA. The next in-frame methionine is located at codon 33. For these reasons, this variant has been classified as Pathogenic. -

RSPH9-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2024

The RSPH9 c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Alternate nucleotide changes affecting the start codon (c.2T>C and c.3G>A) have been reported in the homozygous state in individuals with primary ciliary dyskinesia (Frommer et al. 2015. PubMed ID: 25789548; Table S1, Kott et al. 2013. PubMed ID: 23993197). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Benign

-0.65

MutationTaster

Benign

1.0

D;D

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.71

.;P

Vest4

0.94

MutPred

0.99

Loss of stability (P = 0.1235);Loss of stability (P = 0.1235);

MVP

0.79

ClinPred

1.0

GERP RS

4.9

Varity_R

0.93

gMVP

0.95

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

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

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