rs2839536

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_080860.4(RSPH1):c.393G>A(p.Ala131Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,626 control chromosomes in the GnomAD database, including 125,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9560 hom., cov: 33)

Exomes 𝑓: 0.39 ( 115763 hom. )

Consequence

RSPH1
NM_080860.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.39

Publications

22 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 21-42485777-C-T is Benign according to our data. Variant chr21-42485777-C-T is described in ClinVar as Benign. ClinVar VariationId is 227050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4 link	c.393G>A	p.Ala131Ala	synonymous_variant	Exon 5 of 9	ENST00000291536.8	NP_543136.1	Q8WYR4-1
RSPH1	NM_001286506.2 link	c.279G>A	p.Ala93Ala	synonymous_variant	Exon 4 of 8		NP_001273435.1	Q8WYR4-2
RSPH1	XM_011529786.2 link	c.393G>A	p.Ala131Ala	synonymous_variant	Exon 5 of 8		XP_011528088.1
RSPH1	XM_005261208.3 link	c.186G>A	p.Ala62Ala	synonymous_variant	Exon 3 of 7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH1	ENST00000291536.8 link	c.393G>A	p.Ala131Ala	synonymous_variant	Exon 5 of 9	1	NM_080860.4	ENSP00000291536.3	Q8WYR4-1
RSPH1	ENST00000398352.3 link	c.279G>A	p.Ala93Ala	synonymous_variant	Exon 4 of 8	5		ENSP00000381395.3	Q8WYR4-2
RSPH1	ENST00000493019.1 link	n.1019G>A		non_coding_transcript_exon_variant	Exon 4 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49473

AN:

151918

Hom.:

9559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.475

Gnomad AMR

AF:

0.533

Gnomad ASJ

AF:

0.358

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.296

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.346

GnomAD2 exomes

AF:

0.382

AC:

96012

AN:

251430

AF XY:

0.373

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.673

Gnomad ASJ exome

AF:

0.344

Gnomad EAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.389

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.386

GnomAD4 exome

AF:

0.389

AC:

568517

AN:

1461588

Hom.:

115763

Cov.:

AF XY:

0.385

AC XY:

279789

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.120

AC:

4002

AN:

33472

American (AMR)

AF:

0.653

AC:

29183

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

9005

AN:

26134

East Asian (EAS)

AF:

0.183

AC:

7250

AN:

39696

South Asian (SAS)

AF:

0.295

AC:

25418

AN:

86254

European-Finnish (FIN)

AF:

0.385

AC:

20560

AN:

53388

Middle Eastern (MID)

AF:

0.254

AC:

1467

AN:

5766

European-Non Finnish (NFE)

AF:

0.404

AC:

449391

AN:

1111772

Other (OTH)

AF:

0.368

AC:

22241

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

17689

35379

53068

70758

88447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13910

27820

41730

55640

69550

<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:

0.326

AC:

49492

AN:

152038

Hom.:

9560

Cov.:

AF XY:

0.328

AC XY:

24348

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.132

AC:

5460

AN:

41498

American (AMR)

AF:

0.533

AC:

8144

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.358

AC:

1244

AN:

3472

East Asian (EAS)

AF:

0.192

AC:

992

AN:

5174

South Asian (SAS)

AF:

0.297

AC:

1433

AN:

4820

European-Finnish (FIN)

AF:

0.386

AC:

4066

AN:

10530

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.396

AC:

26927

AN:

67960

Other (OTH)

AF:

0.342

AC:

720

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1579

3157

4736

6314

7893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.372

Hom.:

44094

Bravo

AF:

0.330

Asia WGS

AF:

0.234

AC:

818

AN:

3478

EpiCase

AF:

0.388

EpiControl

AF:

0.384

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala131Ala in exon 5 of RSPH1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 39.3% (3379/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2839536). -

Primary ciliary dyskinesia 24

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.29

(source)

DANN

Benign

0.86

PhyloP100

-2.4

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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