21-42477368-A-C

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.650T>G(p.Leu217Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00858 in 1,610,502 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L217F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0070 ( 10 hom., cov: 34)

Exomes 𝑓: 0.0087 ( 66 hom. )

Consequence

RSPH1
NM_080860.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.22

Publications

13 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=0.009697765).

BP6

Variant 21-42477368-A-C is Benign according to our data. Variant chr21-42477368-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241788.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 = 0.00704 (1048/148776) while in subpopulation NFE AF = 0.0108 (718/66742). AF 95% confidence interval is 0.0101. There are 10 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4 link	c.650T>G	p.Leu217Trp	missense_variant	Exon 7 of 9	ENST00000291536.8	NP_543136.1	Q8WYR4-1
RSPH1	NM_001286506.2 link	c.536T>G	p.Leu179Trp	missense_variant	Exon 6 of 8		NP_001273435.1	Q8WYR4-2
RSPH1	XM_011529786.2 link	c.578T>G	p.Leu193Trp	missense_variant	Exon 6 of 8		XP_011528088.1
RSPH1	XM_005261208.3 link	c.443T>G	p.Leu148Trp	missense_variant	Exon 5 of 7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH1	ENST00000291536.8 link	c.650T>G	p.Leu217Trp	missense_variant	Exon 7 of 9	1	NM_080860.4	ENSP00000291536.3	Q8WYR4-1
RSPH1	ENST00000398352.3 link	c.536T>G	p.Leu179Trp	missense_variant	Exon 6 of 8	5		ENSP00000381395.3	Q8WYR4-2
RSPH1	ENST00000493019.1 link	n.2268T>G		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.00705

AC:

1048

AN:

148660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.0100

Gnomad AMR

AF:

0.00921

Gnomad ASJ

AF:

0.0201

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00300

Gnomad FIN

AF:

0.000681

Gnomad MID

AF:

0.0288

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.00885

GnomAD2 exomes

AF:

0.00733

AC:

1843

AN:

251392

AF XY:

0.00781

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00471

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00897

GnomAD4 exome

AF:

0.00874

AC:

12778

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00882

AC XY:

6413

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33476

American (AMR)

AF:

0.00445

AC:

199

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

468

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00534

AC:

461

AN:

86256

European-Finnish (FIN)

AF:

0.00180

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.0199

AC:

115

AN:

5768

European-Non Finnish (NFE)

AF:

0.00971

AC:

10800

AN:

1111912

Other (OTH)

AF:

0.00997

AC:

602

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

689

1379

2068

2758

3447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

380

760

1140

1520

1900

<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:

0.00704

AC:

1048

AN:

148776

Hom.:

Cov.:

AF XY:

0.00664

AC XY:

482

AN XY:

72580

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

40448

American (AMR)

AF:

0.00920

AC:

137

AN:

14888

Ashkenazi Jewish (ASJ)

AF:

0.0201

AC:

AN:

3426

East Asian (EAS)

AF:

0.00

AC:

AN:

5074

South Asian (SAS)

AF:

0.00300

AC:

AN:

4666

European-Finnish (FIN)

AF:

0.000681

AC:

AN:

10286

Middle Eastern (MID)

AF:

0.0310

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0108

AC:

718

AN:

66742

Other (OTH)

AF:

0.00827

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

120

179

239

299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00992

Hom.:

Bravo

AF:

0.00730

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00727

AC:

883

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 02, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RSPH1: BS2 -

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

Leu217Trp in exon 7 of RSPH1: This variant is not expected to have clinical sign ificance because it has been identified in 1.0% (87/8600) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs138007679). -

Primary ciliary dyskinesia 24

Benign:1

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:1

Feb 02, 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

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.52

D;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0097

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

5.2

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.69

MVP

0.65

MPC

0.64

ClinPred

0.045

GERP RS

4.3

Varity_R

0.18

gMVP

0.75

Mutation Taster

=90/10

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