rs10455840

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031924.8(RSPH3):c.767G>A(p.Arg256Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,614,062 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 32)

Exomes 𝑓: 0.022 ( 381 hom. )

Consequence

RSPH3
NM_031924.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.792

Publications

12 publications found

Variant links:

Genes affected

RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

RSPH3 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 32
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RSPH3 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=0.0036847591).

BP6

Variant 6-158980866-C-T is Benign according to our data. Variant chr6-158980866-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0178 (2709/152254) while in subpopulation NFE AF = 0.0237 (1612/68012). AF 95% confidence interval is 0.0227. There are 34 homozygotes in GnomAd4. There are 1287 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH3	NM_031924.8 link	c.767G>A	p.Arg256Gln	missense_variant	Exon 6 of 8	ENST00000367069.7	NP_114130.4	Q86UC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7 link	c.767G>A	p.Arg256Gln	missense_variant	Exon 6 of 8	1	NM_031924.8	ENSP00000356036.1		A0A0C4DFU3
RSPH3	ENST00000449822.6 link	c.479G>A	p.Arg160Gln	missense_variant	Exon 4 of 6	2		ENSP00000393195.1		A0A0C4DG29

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2707

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00929

Gnomad AMI

AF:

0.0934

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0167

AC:

4211

AN:

251470

AF XY:

0.0171

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0171

GnomAD4 exome

AF:

0.0216

AC:

31621

AN:

1461808

Hom.:

381

Cov.:

AF XY:

0.0213

AC XY:

15456

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0101

AC:

339

AN:

33478

American (AMR)

AF:

0.0152

AC:

680

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00746

AC:

195

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39696

South Asian (SAS)

AF:

0.0127

AC:

1096

AN:

86250

European-Finnish (FIN)

AF:

0.0155

AC:

830

AN:

53420

Middle Eastern (MID)

AF:

0.0248

AC:

143

AN:

5766

European-Non Finnish (NFE)

AF:

0.0245

AC:

27200

AN:

1111946

Other (OTH)

AF:

0.0187

AC:

1129

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1514

3028

4542

6056

7570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1016

2032

3048

4064

5080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0178

AC:

2709

AN:

152254

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1287

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00931

AC:

387

AN:

41552

American (AMR)

AF:

0.0233

AC:

357

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00851

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0155

AC:

164

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0237

AC:

1612

AN:

68012

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

141

283

424

566

707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0213

Hom.:

124

Bravo

AF:

0.0179

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0236

AC:

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.0245

AC:

211

ExAC

AF:

0.0167

AC:

2026

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0250

EpiControl

AF:

0.0240

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 32

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Oct 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.056

T;.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.86

D;D;D

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

.;.;M

PhyloP100

0.79

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.037

Sift

Benign

0.22

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.10

.;.;B

Vest4

0.12

MPC

0.39

ClinPred

0.025

GERP RS

-0.62

Varity_R

0.053

gMVP

0.57

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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