rs151158140

Variant names:

Variant summary

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

The NM_080860.4(RSPH1):c.733G>A(p.Gly245Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,613,710 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0058 ( 31 hom. )

Consequence

RSPH1
NM_080860.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.462

Publications

12 publications found

Variant links:

Genes affected

RSPH1 (HGNC:12371): (radial spoke head component 1) This gene encodes a male meiotic metaphase chromosome-associated acidic protein. This gene is expressed in tissues with motile cilia or flagella, including the trachea, lungs, airway brushings, and testes. Mutations in this gene result in primary ciliary dyskinesia-24. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

RSPH1 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 24
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RSPH1 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=0.005465418).

BP6

Variant 21-42476042-C-T is Benign according to our data. Variant chr21-42476042-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00449 (683/151968) while in subpopulation AMR AF = 0.0113 (173/15272). AF 95% confidence interval is 0.00995. There are 1 homozygotes in GnomAd4. There are 304 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 31 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RSPH1	NM_080860.4 link	c.733G>A	p.Gly245Arg	missense_variant	Exon 8 of 9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2 link	c.619G>A	p.Gly207Arg	missense_variant	Exon 7 of 8		NP_001273435.1
RSPH1	XM_011529786.2 link	c.661G>A	p.Gly221Arg	missense_variant	Exon 7 of 8		XP_011528088.1
RSPH1	XM_005261208.3 link	c.526G>A	p.Gly176Arg	missense_variant	Exon 6 of 7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RSPH1	ENST00000291536.8 link	c.733G>A	p.Gly245Arg	missense_variant	Exon 8 of 9	1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3 link	c.619G>A	p.Gly207Arg	missense_variant	Exon 7 of 8	5		ENSP00000381395.3
RSPH1	ENST00000493019.1 link	n.2351G>A		non_coding_transcript_exon_variant	Exon 7 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.00450

AC:

683

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00586

Gnomad OTH

AF:

0.00433

GnomAD2 exomes

AF:

0.00385

AC:

967

AN:

251258

AF XY:

0.00378

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00530

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00605

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00583

AC:

8524

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00567

AC XY:

4122

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

33478

American (AMR)

AF:

0.00492

AC:

220

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00266

AC:

142

AN:

53374

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00704

AC:

7824

AN:

1111926

Other (OTH)

AF:

0.00474

AC:

286

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

399

797

1196

1594

1993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.00449

AC:

683

AN:

151968

Hom.:

Cov.:

AF XY:

0.00409

AC XY:

304

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41474

American (AMR)

AF:

0.0113

AC:

173

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5100

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00208

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00586

AC:

398

AN:

67960

Other (OTH)

AF:

0.00429

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00507

Hom.:

Bravo

AF:

0.00487

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00343

AC:

416

EpiCase

AF:

0.00469

EpiControl

AF:

0.00587

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.0055

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

0.46

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.013

D;D

Sift4G

Benign

0.082

T;T

Polyphen

0.92

P;.

Vest4

0.33

MutPred

0.32

Gain of loop (P = 0.0045);.;

MVP

0.34

MPC

0.32

ClinPred

0.015

GERP RS

1.5

Varity_R

0.082

gMVP

0.30

Mutation Taster

=99/1

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over