chr6-43670942-TG-AT

Variant names:

• chr6-43670942-TG-AT
• rs727503395
• NM_152732.5:c.824_825delTGinsAT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_152732.5(RSPH9):​c.824_825delTGinsAT​(p.Met275Asn) variant causes a missense change involving the alteration of a 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 MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M275I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RSPH9 NM_152732.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 12

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH9	NM_152732.5	c.824_825delTGinsAT	p.Met275Asn	missense_variant		ENST00000372163.5	NP_689945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH9	ENST00000372163.5	c.824_825delTGinsAT	p.Met275Asn	missense_variant		1	NM_152732.5	ENSP00000361236.4
RSPH9	ENST00000372165.8	c.876_877delTGinsAT	p.HisAla292GlnSer	missense_variant		2		ENSP00000361238.4

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 30, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The His292_Ala293delinsGlnSer variant in RSPH9 has not been reported in individu als with pulmonary disease or in large population studies. This variant changes two adjacent bases leading to a replacement of Histidine (His) and Alanine (Ala) at positions 292-293 with Glutamine (Gln) and Serine (Ser).Computational analys es (biochemical amino acid properties, evolutionary conservation, AlignGVGD, Pol yPhen2, and SIFT) do not provide strong support for or against an impact to the protein based on either amino acid change. Of note, neither the His292Gln nor th e Ala293Ser variants have independently been reported in individuals with pulmon ary disease or in large population studies. In summary, additional studies are n eeded to fully assess the clinical significance of the His292_Ala293delinsGlnSer variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

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

Other links and lift over

dbSNP: rs727503395; hg19: chr6-43638679;