6-116617207-C-G

Position:

chr6-116617207-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001010892.3(RSPH4A):c.584C>G(p.Pro195Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 0 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.418

Variant links:

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 links:

RSPH4A (HGNC:):

RSPH4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020517707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3 linkuse as main transcript	c.584C>G	p.Pro195Arg	missense_variant	1/6	ENST00000229554.10	NP_001010892.1	Q5TD94-1B3KTA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RSPH4A	ENST00000229554.10 linkuse as main transcript	c.584C>G	p.Pro195Arg	missense_variant	1/6	1	NM_001010892.3	ENSP00000229554.5	Q5TD94-1
RSPH4A	ENST00000368581.8 linkuse as main transcript	c.584C>G	p.Pro195Arg	missense_variant	1/5	1		ENSP00000357570.4	Q5TD94-3
RSPH4A	ENST00000368580.4 linkuse as main transcript	c.584C>G	p.Pro195Arg	missense_variant	1/5	5		ENSP00000357569.4	Q5TD94-2

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000492

AC:

123

AN:

250078

Hom.:

AF XY:

0.000502

AC XY:

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.0000632

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000579

AC:

846

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000562

AC XY:

409

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000722

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000401

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000753

Hom.:

Bravo

AF:

0.000521

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000610

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jan 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2018	The p.P195R variant (also known as c.584C>G), located in coding exon 1 of the RSPH4A gene, results from a C to G substitution at nucleotide position 584. The proline at codon 195 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 195 of the RSPH4A protein (p.Pro195Arg). This variant is present in population databases (rs141226759, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RSPH4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 165058). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 01, 2014

Variant classified as Uncertain Significance - Favor Benign. The Pro195Arg varia nt in RSPH4A has not been previously reported in individuals with pulmonary dise ase, but has been identified in 0.093% (8/8600) of European American chromosomes and 0.045% (2/4406) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs141226759). Computational prediction tools and conservation analysis suggest that the Pro195Arg variant m ay not impact the protein, though this information is not predictive enough to r ule out pathogenicity. In summary, while the clinical significance of the Pro195 Arg variant is uncertain, these data suggest that it is more likely to be benign . -

Primary ciliary dyskinesia 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

.;T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;L

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Benign

0.047

Sift

Benign

0.053

T;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.83

P;P;.

Vest4

0.21

MVP

0.66

MPC

0.46

ClinPred

0.052

GERP RS

2.5

Varity_R

0.073

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over