dbSNP rs12204826: RSPH3:p.Glu342Lys (chr6-158977771-C-T) – ACMG Classification: Benign (-20 pts)

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: 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=0.0032161474).

BP6

Variant 6-158977771-C-T is Benign according to our data. Variant chr6-158977771-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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

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.1024G>A	p.Glu342Lys	missense	Exon 8 of 8	NP_114130.4
RSPH3	NM_001346418.1		c.1162G>A	p.Glu388Lys	missense	Exon 6 of 6	NP_001333347.1	Q86UC2-2
RSPH3	NR_144434.1		n.1661G>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.1024G>A	p.Glu342Lys	missense	Exon 8 of 8	ENSP00000356036.1	A0A0C4DFU3
RSPH3	ENST00000884885.1		c.856G>A	p.Glu286Lys	missense	Exon 7 of 7	ENSP00000554944.1
RSPH3	ENST00000449822.6	TSL:2	c.736G>A	p.Glu246Lys	missense	Exon 6 of 6	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

Age Distribution

Exome Het

Exome Hom

Variant carriers

1022

2044

3066

4088

5110

<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:

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

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:

0.0211

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Primary ciliary dyskinesia 32 (2)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

PhyloP100

-0.63

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.017

Sift

Benign

0.14

Sift4G

Benign

0.34

Polyphen

0.052

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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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