chr21-42475905-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS1

The NM_080860.4(RSPH1):c.870G>A(p.Met290Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,611,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 28)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

RSPH1
NM_080860.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -2.80

Publications

1 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035790205).

BP6

Variant 21-42475905-C-T is Benign according to our data. Variant chr21-42475905-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 241792.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00122 (182/149232) while in subpopulation AFR AF = 0.00435 (177/40654). AF 95% confidence interval is 0.00383. There are 1 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	NM_080860.4	MANE Select	c.870G>A	p.Met290Ile	missense	Exon 8 of 9	NP_543136.1
	RSPH1	NM_001286506.2		c.756G>A	p.Met252Ile	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.870G>A	p.Met290Ile	missense	Exon 8 of 9	ENSP00000291536.3
RSPH1	ENST00000398352.3	TSL:5	c.756G>A	p.Met252Ile	missense	Exon 7 of 8	ENSP00000381395.3
RSPH1	ENST00000493019.1	TSL:2	n.2488G>A		non_coding_transcript_exon	Exon 7 of 8

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

182

AN:

149114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000204

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00100

GnomAD2 exomes

AF:

0.000346

AC:

AN:

251410

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.00504

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000130

AC:

190

AN:

1461826

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00496

AC:

166

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111974

Other (OTH)

AF:

0.000215

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00122

AC:

182

AN:

149232

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

72608

show subpopulations

African (AFR)

AF:

0.00435

AC:

177

AN:

40654

American (AMR)

AF:

0.000203

AC:

AN:

14754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

4964

South Asian (SAS)

AF:

0.00

AC:

AN:

4290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67462

Other (OTH)

AF:

0.000991

AC:

AN:

2018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000575

Hom.:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000453

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RSPH1-related disorder

Benign:1

Apr 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.038

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.029

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.35

M_CAP

Benign

0.019

MetaRNN

Benign

0.0036

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.60

PhyloP100

-2.8

PrimateAI

Benign

0.33

PROVEAN

Benign

0.12

REVEL

Benign

0.035

Sift

Benign

1.0

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.11

MutPred

0.19

Loss of phosphorylation at Y288 (P = 0.131)

MVP

0.040

MPC

0.11

ClinPred

0.0052

GERP RS

-5.7

Varity_R

0.041

gMVP

0.069

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over