rs146142715

Positions:

chr6-116632280-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000229554.10(RSPH4A):c.1990C>T(p.Pro664Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,978 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 8 hom. )

Consequence

RSPH4A
ENST00000229554.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.0220

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:

LOC124901386 (HGNC:):

LOC124901386 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008825988).

BP6

Variant 6-116632280-C-T is Benign according to our data. Variant chr6-116632280-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 355124.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3 linkuse as main transcript	c.1990C>T	p.Pro664Ser	missense_variant	6/6	ENST00000229554.10	NP_001010892.1
LOC124901386	XR_007059721.1 linkuse as main transcript	n.459+1525G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10 linkuse as main transcript	c.1990C>T	p.Pro664Ser	missense_variant	6/6	1	NM_001010892.3	ENSP00000229554	P1	Q5TD94-1
RSPH4A	ENST00000368581.8 linkuse as main transcript	c.*51C>T		3_prime_UTR_variant	5/5	1		ENSP00000357570		Q5TD94-3
RSPH4A	ENST00000368580.4 linkuse as main transcript	c.1249C>T	p.Pro417Ser	missense_variant	5/5	5		ENSP00000357569		Q5TD94-2

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

180

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00444

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00156

AC:

392

AN:

251346

Hom.:

AF XY:

0.00163

AC XY:

222

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000849

Gnomad FIN exome

AF:

0.00328

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00143

AC:

2092

AN:

1460802

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

1018

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00398

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000673

Gnomad4 FIN exome

AF:

0.00348

Gnomad4 NFE exome

AF:

0.00143

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00118

AC:

180

AN:

152176

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00444

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00180

AC:

219

EpiCase

AF:

0.00131

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Eurofins Ntd Llc (ga)

Oct 06, 2016

- -

RSPH4A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary ciliary dyskinesia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Benign

0.16

Sift

Benign

0.12

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.90

P;.

Vest4

0.13

MVP

0.68

MPC

0.21

ClinPred

0.093

GERP RS

5.1

Varity_R

0.23

gMVP

0.45

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