NM_001010892.3:c.166dupC

Variant names:

• chr6-116616786-T-TC
• rs797045147
• NM_001010892.3:c.166dupC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001010892.3(RSPH4A):​c.166dupC​(p.Arg56ProfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RSPH4A NM_001010892.3 frameshift
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.666
• Publications: 2 publications found

Genes affected

RSPH4A (HGNC:21558): (radial spoke head component 4A) This gene encodes a protein that appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein. Mutations in this gene cause primary ciliary dyskinesia 1, a disease arising from dysmotility of motile cilia and sperm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

RSPH4A Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 11

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010892.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH4A	NM_001010892.3	MANE Select	c.166dupC	p.Arg56ProfsTer11	frameshift	Exon 1 of 6	NP_001010892.1
	RSPH4A	NM_001161664.2		c.166dupC	p.Arg56ProfsTer11	frameshift	Exon 1 of 5	NP_001155136.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH4A	ENST00000229554.10	TSL:1 MANE Select	c.166dupC	p.Arg56ProfsTer11	frameshift	Exon 1 of 6	ENSP00000229554.5
	RSPH4A	ENST00000368581.8	TSL:1	c.166dupC	p.Arg56ProfsTer11	frameshift	Exon 1 of 5	ENSP00000357570.4
	RSPH4A	ENST00000368580.4	TSL:5	c.166dupC	p.Arg56ProfsTer11	frameshift	Exon 1 of 5	ENSP00000357569.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Kartagener syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797045147; hg19: chr6-116937949;