rs6927567

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001010892.3(RSPH4A):c.1667G>A(p.Arg556His) variant causes a missense change. The variant allele was found at a frequency of 0.199 in 1,608,588 control chromosomes in the GnomAD database, including 33,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R556C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.19 ( 2822 hom., cov: 32)

Exomes 𝑓: 0.20 ( 30364 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.84

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022907257).

BP6

Variant 6-116629571-G-A is Benign according to our data. Variant chr6-116629571-G-A is described in ClinVar as [Benign]. Clinvar id is 165060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116629571-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH4A	NM_001010892.3 linkuse as main transcript	c.1667G>A	p.Arg556His	missense_variant	4/6	ENST00000229554.10
LOC124901386	XR_007059721.1 linkuse as main transcript	n.879C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH4A	ENST00000229554.10 linkuse as main transcript	c.1667G>A	p.Arg556His	missense_variant	4/6	1	NM_001010892.3	P1	Q5TD94-1
RSPH4A	ENST00000368581.8 linkuse as main transcript	c.1663-864G>A		intron_variant		1			Q5TD94-3
RSPH4A	ENST00000368580.4 linkuse as main transcript	c.926G>A	p.Arg309His	missense_variant	3/5	5			Q5TD94-2

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28334

AN:

151838

Hom.:

2819

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.199

GnomAD3 exomes

AF:

0.214

AC:

53235

AN:

248496

Hom.:

5923

AF XY:

0.214

AC XY:

28789

AN XY:

134548

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.300

Gnomad SAS exome

AF:

0.219

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.222

GnomAD4 exome

AF:

0.200

AC:

291692

AN:

1456632

Hom.:

30364

Cov.:

AF XY:

0.201

AC XY:

145604

AN XY:

724974

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.214

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.320

Gnomad4 SAS exome

AF:

0.215

Gnomad4 FIN exome

AF:

0.257

Gnomad4 NFE exome

AF:

0.193

Gnomad4 OTH exome

AF:

0.201

GnomAD4 genome

AF:

0.187

AC:

28347

AN:

151956

Hom.:

2822

Cov.:

AF XY:

0.190

AC XY:

14145

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.202

Gnomad4 ASJ

AF:

0.236

Gnomad4 EAS

AF:

0.291

Gnomad4 SAS

AF:

0.216

Gnomad4 FIN

AF:

0.254

Gnomad4 NFE

AF:

0.199

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.203

Hom.:

7992

Bravo

AF:

0.179

TwinsUK

AF:

0.198

AC:

736

ALSPAC

AF:

0.197

AC:

758

ESP6500AA

AF:

0.120

AC:

529

ESP6500EA

AF:

0.195

AC:

1679

ExAC

AF:

0.213

AC:

25871

Asia WGS

AF:

0.263

AC:

913

AN:

3478

EpiCase

AF:

0.198

EpiControl

AF:

0.202

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg556His in exon 4 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 19.5% (1679/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs6927567). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary ciliary dyskinesia 11

Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.085

T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

4.8e-8

P;P;P

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.80

P;.

Vest4

0.90

MPC

0.70

ClinPred

0.095

GERP RS

5.2

Varity_R

0.77

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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