NM_031924.8:c.1127G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_031924.8(RSPH3):c.1127G>A(p.Gly376Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,613,430 control chromosomes in the GnomAD database, including 20,467 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 Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2042 hom., cov: 32)

Exomes 𝑓: 0.13 ( 18425 hom. )

Consequence

RSPH3
NM_031924.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.887

Publications

32 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: ClinGen, PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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=7.494986E-4).

BP6

Variant 6-158977668-C-T is Benign according to our data. Variant chr6-158977668-C-T is described in ClinVar as Benign. ClinVar VariationId is 1170195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031924.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RSPH3	NM_031924.8	MANE Select	c.1127G>A	p.Gly376Asp	missense	Exon 8 of 8	NP_114130.4
RSPH3	NM_001346418.1		c.1265G>A	p.Gly422Asp	missense	Exon 6 of 6	NP_001333347.1	Q86UC2-2
RSPH3	NR_144434.1		n.1764G>A		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.1127G>A	p.Gly376Asp	missense	Exon 8 of 8	ENSP00000356036.1	A0A0C4DFU3
RSPH3	ENST00000884885.1		c.959G>A	p.Gly320Asp	missense	Exon 7 of 7	ENSP00000554944.1
RSPH3	ENST00000449822.6	TSL:2	c.839G>A	p.Gly280Asp	missense	Exon 6 of 6	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20019

AN:

151990

Hom.:

2032

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0844

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.306

Gnomad ASJ

AF:

0.115

Gnomad EAS

AF:

0.413

Gnomad SAS

AF:

0.203

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0994

Gnomad OTH

AF:

0.140

GnomAD2 exomes

AF:

0.188

AC:

47260

AN:

251352

AF XY:

0.177

show subpopulations

Gnomad AFR exome

AF:

0.0804

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.113

Gnomad EAS exome

AF:

0.401

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.162

GnomAD4 exome

AF:

0.128

AC:

187607

AN:

1461322

Hom.:

18425

Cov.:

AF XY:

0.129

AC XY:

93424

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.0790

AC:

2646

AN:

33478

American (AMR)

AF:

0.471

AC:

21049

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2973

AN:

26128

East Asian (EAS)

AF:

0.463

AC:

18356

AN:

39672

South Asian (SAS)

AF:

0.186

AC:

16044

AN:

86230

European-Finnish (FIN)

AF:

0.104

AC:

5559

AN:

53400

Middle Eastern (MID)

AF:

0.131

AC:

754

AN:

5766

European-Non Finnish (NFE)

AF:

0.101

AC:

112051

AN:

1111576

Other (OTH)

AF:

0.135

AC:

8175

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

8778

17556

26334

35112

43890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4478

8956

13434

17912

22390

<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:

0.132

AC:

20068

AN:

152108

Hom.:

2042

Cov.:

AF XY:

0.137

AC XY:

10195

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0849

AC:

3522

AN:

41498

American (AMR)

AF:

0.306

AC:

4675

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

399

AN:

3470

East Asian (EAS)

AF:

0.414

AC:

2134

AN:

5152

South Asian (SAS)

AF:

0.202

AC:

975

AN:

4820

European-Finnish (FIN)

AF:

0.106

AC:

1128

AN:

10602

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0994

AC:

6759

AN:

67976

Other (OTH)

AF:

0.145

AC:

306

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

798

1597

2395

3194

3992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.121

Hom.:

5144

Bravo

AF:

0.151

TwinsUK

AF:

0.0944

AC:

350

ALSPAC

AF:

0.105

AC:

403

ESP6500AA

AF:

0.0917

AC:

404

ESP6500EA

AF:

0.108

AC:

926

ExAC

AF:

0.175

AC:

21297

Asia WGS

AF:

0.287

AC:

998

AN:

3478

EpiCase

AF:

0.102

EpiControl

AF:

0.105

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Primary ciliary dyskinesia 32 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.4

(source)

DANN

Benign

0.085

DEOGEN2

Benign

0.0018

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.000070

LIST_S2

Benign

0.33

MetaRNN

Benign

0.00075

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.0

PhyloP100

0.89

PrimateAI

Benign

0.27

PROVEAN

Benign

1.6

REVEL

Benign

0.058

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.017

MPC

0.38

ClinPred

0.0040

GERP RS

2.8

Varity_R

0.028

gMVP

0.027

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over