NM_001010892.3:c.1879A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 variant affecting the same amino acid position, but resulting in a different missense (i.e. N627K) has been classified as Uncertain significance.

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

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 11
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RSPH4A links:

LOC124901386 (HGNC:):

LOC124901386 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3 link	c.1879A>C	p.Asn627His	missense_variant	Exon 5 of 6	ENST00000229554.10	NP_001010892.1	Q5TD94-1B3KTA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH4A	ENST00000229554.10 link	c.1879A>C	p.Asn627His	missense_variant	Exon 5 of 6	1	NM_001010892.3	ENSP00000229554.5	Q5TD94-1
RSPH4A	ENST00000368581.8 link	c.1743A>C	p.Pro581Pro	synonymous_variant	Exon 4 of 5	1		ENSP00000357570.4	Q5TD94-3
RSPH4A	ENST00000368580.4 link	c.1138A>C	p.Asn380His	missense_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.0925

AC:

23267

AN:

251438

AF XY:

0.0857

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 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

African (AFR)

AF:

0.251

AC:

8342

AN:

33228

American (AMR)

AF:

0.233

AC:

10435

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0706

AC:

1843

AN:

26088

East Asian (EAS)

AF:

0.0241

AC:

957

AN:

39652

South Asian (SAS)

AF:

0.115

AC:

9894

AN:

86074

European-Finnish (FIN)

AF:

0.0305

AC:

1629

AN:

53414

Middle Eastern (MID)

AF:

0.0469

AC:

270

AN:

5754

European-Non Finnish (NFE)

AF:

0.0477

AC:

52701

AN:

1105816

Other (OTH)

AF:

0.0710

AC:

4270

AN:

60156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4079

8157

12236

16314

20393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.113

AC:

17202

AN:

151944

Hom.:

1643

Cov.:

AF XY:

0.112

AC XY:

8332

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.243

AC:

10062

AN:

41378

American (AMR)

AF:

0.167

AC:

2552

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.0709

AC:

246

AN:

3470

East Asian (EAS)

AF:

0.0225

AC:

116

AN:

5166

South Asian (SAS)

AF:

0.120

AC:

576

AN:

4818

European-Finnish (FIN)

AF:

0.0301

AC:

318

AN:

10570

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0457

AC:

3105

AN:

67982

Other (OTH)

AF:

0.0982

AC:

207

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

698

1396

2094

2792

3490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0688

Hom.:

3329

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

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:2

Dec 24, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 11

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

7.2

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

Mutation Taster

=82/18

polymorphism (auto)

(source)

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

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NM_001010892.3:c.1879A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over