chr6-116630515-A-C

Position:

chr6-116630515-A-C

Variant summary

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

The NM_001010892.3(RSPH4A):c.1879A>C(p.Asn627His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,606,826 control chromosomes in the GnomAD database, including 6,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.11 ( 1643 hom., cov: 31)

Exomes 𝑓: 0.062 ( 4650 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.22

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002024293).

BP6

Variant 6-116630515-A-C is Benign according to our data. Variant chr6-116630515-A-C is described in ClinVar as [Benign]. Clinvar id is 165062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116630515-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3 linkuse as main transcript	c.1879A>C	p.Asn627His	missense_variant	5/6	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.1879A>C	p.Asn627His	missense_variant	5/6	1	NM_001010892.3	ENSP00000229554.5	Q5TD94-1
RSPH4A	ENST00000368581.8 linkuse as main transcript	c.1743A>C	p.Pro581Pro	synonymous_variant	4/5	1		ENSP00000357570.4	Q5TD94-3
RSPH4A	ENST00000368580.4 linkuse as main transcript	c.1138A>C	p.Asn380His	missense_variant	4/5	5		ENSP00000357569.4	Q5TD94-2

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17162

AN:

151826

Hom.:

1633

Cov.:

show subpopulations

Gnomad AFR

AF:

0.243

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.167

Gnomad ASJ

AF:

0.0709

Gnomad EAS

AF:

0.0224

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0301

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0457

Gnomad OTH

AF:

0.0992

GnomAD3 exomes

AF:

0.0925

AC:

23267

AN:

251438

Hom.:

2007

AF XY:

0.0857

AC XY:

11640

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.238

Gnomad ASJ exome

AF:

0.0659

Gnomad EAS exome

AF:

0.0192

Gnomad SAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0463

Gnomad OTH exome

AF:

0.0766

GnomAD4 exome

AF:

0.0621

AC:

90341

AN:

1454882

Hom.:

4650

Cov.:

AF XY:

0.0623

AC XY:

45124

AN XY:

724174

show subpopulations

Gnomad4 AFR exome

AF:

0.251

Gnomad4 AMR exome

AF:

0.233

Gnomad4 ASJ exome

AF:

0.0706

Gnomad4 EAS exome

AF:

0.0241

Gnomad4 SAS exome

AF:

0.115

Gnomad4 FIN exome

AF:

0.0305

Gnomad4 NFE exome

AF:

0.0477

Gnomad4 OTH exome

AF:

0.0710

GnomAD4 genome

AF:

0.113

AC:

17202

AN:

151944

Hom.:

1643

Cov.:

AF XY:

0.112

AC XY:

8332

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.243

Gnomad4 AMR

AF:

0.167

Gnomad4 ASJ

AF:

0.0709

Gnomad4 EAS

AF:

0.0225

Gnomad4 SAS

AF:

0.120

Gnomad4 FIN

AF:

0.0301

Gnomad4 NFE

AF:

0.0457

Gnomad4 OTH

AF:

0.0982

Alfa

AF:

0.0616

Hom.:

1305

Bravo

AF:

0.131

TwinsUK

AF:

0.0572

AC:

212

ALSPAC

AF:

0.0535

AC:

206

ESP6500AA

AF:

0.227

AC:

999

ESP6500EA

AF:

0.0521

AC:

448

ExAC

AF:

0.0901

AC:

10933

Asia WGS

AF:

0.0860

AC:

301

AN:

3478

EpiCase

AF:

0.0463

EpiControl

AF:

0.0487

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Asn627His in exon 5 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 22.7% (999/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs9488991). -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 24, 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

Feb 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.44

MPC

0.63

ClinPred

0.030

GERP RS

5.5

Varity_R

0.77

gMVP

0.79

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