NM_031924.8:c.1024G>A

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.1024G>A(p.Glu342Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,614,090 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 ( 387 hom. )

Consequence

RSPH3
NM_031924.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.625

Publications

16 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=0.0032161474).

BP6

Variant 6-158977771-C-T is Benign according to our data. Variant chr6-158977771-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475824.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 (2718/152270) while in subpopulation NFE AF = 0.0238 (1616/68022). AF 95% confidence interval is 0.0228. There are 34 homozygotes in GnomAd4. There are 1293 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.1024G>A	p.Glu342Lys	missense_variant	Exon 8 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.1024G>A	p.Glu342Lys	missense_variant	Exon 8 of 8	1	NM_031924.8	ENSP00000356036.1		A0A0C4DFU3
RSPH3	ENST00000449822.6 link	c.736G>A	p.Glu246Lys	missense_variant	Exon 6 of 6	2		ENSP00000393195.1		A0A0C4DG29

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2716

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00927

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0236

Gnomad ASJ

AF:

0.00664

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0168

AC:

4213

AN:

251332

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:

0.000217

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0230

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0217

AC:

31768

AN:

1461820

Hom.:

387

Cov.:

AF XY:

0.0213

AC XY:

15519

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0102

AC:

340

AN:

33480

American (AMR)

AF:

0.0152

AC:

680

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00746

AC:

195

AN:

26136

East Asian (EAS)

AF:

0.000202

AC:

AN:

39700

South Asian (SAS)

AF:

0.0127

AC:

1095

AN:

86254

European-Finnish (FIN)

AF:

0.0155

AC:

830

AN:

53416

Middle Eastern (MID)

AF:

0.0248

AC:

143

AN:

5768

European-Non Finnish (NFE)

AF:

0.0246

AC:

27348

AN:

1111950

Other (OTH)

AF:

0.0187

AC:

1129

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1610

3220

4831

6441

8051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0178

AC:

2718

AN:

152270

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

1293

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00929

AC:

386

AN:

41568

American (AMR)

AF:

0.0236

AC:

361

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00664

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00871

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0155

AC:

164

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0238

AC:

1616

AN:

68022

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

145

291

436

582

727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0211

Hom.:

164

Bravo

AF:

0.0180

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0236

AC:

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.0245

AC:

211

ExAC

AF:

0.0167

AC:

2027

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0241

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

May 15, 2025

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

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

0.062

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.3

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.020

T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.49

T;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

.;.;N

PhyloP100

-0.63

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.017

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.052

.;.;B

Vest4

0.028

MPC

0.33

ClinPred

0.0022

GERP RS

-0.71

Varity_R

0.045

gMVP

0.16

Mutation Taster

=98/2

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_031924.8:c.1024G>A

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