rs772035250

Positions:

• chr6-158982495-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031924.8(RSPH3):​c.686G>A​(p.Arg229Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,449,370 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.125

Genes affected

RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

RSPH3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06882912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH3	NM_031924.8	c.686G>A	p.Arg229Gln	missense_variant	5/8	ENST00000367069.7	NP_114130.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7	c.686G>A	p.Arg229Gln	missense_variant	5/8	1	NM_031924.8	ENSP00000356036.1
RSPH3	ENST00000449822.5	c.398G>A	p.Arg133Gln	missense_variant	3/6	2		ENSP00000393195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 244762 Hom.: 0 AF XY: 0.00000752 AC XY: 1 AN XY: 133038

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000248 AC: 36 AN: 1449370 Hom.: 1 Cov.: 30 AF XY: 0.0000180 AC XY: 13 AN XY: 721628

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000379

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000723

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 32 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 475819). This variant has not been reported in the literature in individuals affected with RSPH3-related conditions. This variant is present in population databases (rs772035250, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 371 of the RSPH3 protein (p.Arg371Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	.;.;L
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.76	.;.;P
Vest4		0.18
MutPred		0.45		.;.;Loss of MoRF binding (P = 0.0423);
MVP		0.11
MPC		0.45
ClinPred		0.23	T
GERP RS		0.98
Varity_R		0.097
gMVP		0.28

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: rs772035250; hg19: chr6-159403527; COSMIC: COSV51923135;