21-42476033-C-T

Variant names:

Variant summary

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

The NM_080860.4(RSPH1):c.742G>A(p.Gly248Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,613,276 control chromosomes in the GnomAD database, including 28,399 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1777 hom., cov: 29)

Exomes 𝑓: 0.19 ( 26622 hom. )

Consequence

RSPH1
NM_080860.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.745

Publications

19 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=7.7182055E-4).

BP6

Variant 21-42476033-C-T is Benign according to our data. Variant chr21-42476033-C-T is described in ClinVar as Benign. ClinVar VariationId is 227052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080860.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	NM_080860.4	MANE Select	c.742G>A	p.Gly248Arg	missense	Exon 8 of 9	NP_543136.1
	RSPH1	NM_001286506.2		c.628G>A	p.Gly210Arg	missense	Exon 7 of 8	NP_001273435.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RSPH1	ENST00000291536.8	TSL:1 MANE Select	c.742G>A	p.Gly248Arg	missense	Exon 8 of 9	ENSP00000291536.3
RSPH1	ENST00000856519.1		c.670G>A	p.Gly224Arg	missense	Exon 7 of 8	ENSP00000526578.1
RSPH1	ENST00000398352.3	TSL:5	c.628G>A	p.Gly210Arg	missense	Exon 7 of 8	ENSP00000381395.3

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20062

AN:

151566

Hom.:

1777

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0348

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.192

Gnomad EAS

AF:

0.00765

Gnomad SAS

AF:

0.152

Gnomad FIN

AF:

0.151

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.191

Gnomad OTH

AF:

0.134

GnomAD2 exomes

AF:

0.155

AC:

39048

AN:

251262

AF XY:

0.159

show subpopulations

Gnomad AFR exome

AF:

0.0321

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.178

Gnomad EAS exome

AF:

0.00522

Gnomad FIN exome

AF:

0.154

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.180

GnomAD4 exome

AF:

0.185

AC:

270412

AN:

1461592

Hom.:

26622

Cov.:

AF XY:

0.185

AC XY:

134200

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.0293

AC:

981

AN:

33480

American (AMR)

AF:

0.159

AC:

7093

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

4729

AN:

26130

East Asian (EAS)

AF:

0.00846

AC:

336

AN:

39698

South Asian (SAS)

AF:

0.153

AC:

13159

AN:

86256

European-Finnish (FIN)

AF:

0.158

AC:

8444

AN:

53378

Middle Eastern (MID)

AF:

0.158

AC:

910

AN:

5768

European-Non Finnish (NFE)

AF:

0.202

AC:

224655

AN:

1111788

Other (OTH)

AF:

0.167

AC:

10105

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

11152

22303

33455

44606

55758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7686

15372

23058

30744

38430

<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:

20059

AN:

151684

Hom.:

1777

Cov.:

AF XY:

0.130

AC XY:

9622

AN XY:

74102

show subpopulations

African (AFR)

AF:

0.0347

AC:

1437

AN:

41404

American (AMR)

AF:

0.135

AC:

2065

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

664

AN:

3462

East Asian (EAS)

AF:

0.00767

AC:

AN:

5086

South Asian (SAS)

AF:

0.152

AC:

723

AN:

4744

European-Finnish (FIN)

AF:

0.151

AC:

1590

AN:

10560

Middle Eastern (MID)

AF:

0.123

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.191

AC:

12942

AN:

67882

Other (OTH)

AF:

0.132

AC:

277

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

811

1622

2433

3244

4055

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:

0.174

Hom.:

7996

Bravo

AF:

0.128

TwinsUK

AF:

0.214

AC:

794

ALSPAC

AF:

0.203

AC:

784

ESP6500AA

AF:

0.0361

AC:

159

ESP6500EA

AF:

0.192

AC:

1647

ExAC

AF:

0.155

AC:

18776

Asia WGS

AF:

0.0760

AC:

264

AN:

3478

EpiCase

AF:

0.196

EpiControl

AF:

0.186

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Primary ciliary dyskinesia (1)

Primary ciliary dyskinesia 24 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.056

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.50

MetaRNN

Benign

0.00077

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

-0.74

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.6

REVEL

Benign

0.077

Sift

Benign

0.53

Sift4G

Benign

0.092

Polyphen

0.0030

Vest4

0.027

MutPred

0.29

Loss of loop (P = 0.0075)

MPC

0.12

ClinPred

0.0025

GERP RS

-0.71

Varity_R

0.037

gMVP

0.19

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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