6-43645099-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.96

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 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 [Pathogenic] in ClinVar as 2887444
• 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	UniProt
RSPH9	NM_152732.5	c.1A>G	p.Met1?	start_lost	1/5	ENST00000372163.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH9	ENST00000372163.5	c.1A>G	p.Met1?	start_lost	1/5	1	NM_152732.5	P1
RSPH9	ENST00000372165.8	c.1A>G	p.Met1?	start_lost	1/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458614 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725780

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.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-0.65	T
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	D
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

Other links and lift over

dbSNP: rs775745422; hg19: chr6-43612836;