6-116630450-C-G

Variant names:

• chr6-116630450-C-G
• rs775186734
• NM_001010892.3:c.1814C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001010892.3(RSPH4A):​c.1814C>G​(p.Pro605Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. 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. P605H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 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

LOC124901386 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28230906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.1814C>G	p.Pro605Arg	missense_variant	Exon 5 of 6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1814C>G	p.Pro605Arg	missense_variant	Exon 5 of 6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.1678C>G	p.Pro560Ala	missense_variant	Exon 4 of 5	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.1073C>G	p.Pro358Arg	missense_variant	Exon 4 of 5	5		ENSP00000357569.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1436962 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 716464

African (AFR) AF: 0.0000304 AC: 1 AN: 32928

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 85802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089362

Other (OTH) AF: 0.00 AC: 0 AN: 59538

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RSPH4A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 605 of the RSPH4A protein (p.Pro605Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Benign	0.80
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
PhyloP100		7.7
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.15
Sift	Benign	0.34	T
Sift4G	Benign	0.36	T
Polyphen		0.24	B
Vest4		0.28
MutPred		0.66		Gain of loop (P = 0.0097);
MVP		0.84
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.54
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs775186734; hg19: chr6-116951613;