rs200861411

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_080860.4(RSPH1):c.57A>T(p.Glu19Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

RSPH1
NM_080860.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.712

Publications

2 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06801295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4 link	c.57A>T	p.Glu19Asp	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000291536.8	NP_543136.1	Q8WYR4-1
RSPH1	XM_011529786.2 link	c.57A>T	p.Glu19Asp	missense_variant, splice_region_variant	Exon 2 of 8		XP_011528088.1
RSPH1	NM_001286506.2 link	c.55-214A>T		intron_variant	Intron 1 of 7		NP_001273435.1	Q8WYR4-2
RSPH1	XM_005261208.3 link	c.67+3043A>T		intron_variant	Intron 1 of 6		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH1	ENST00000291536.8 link	c.57A>T	p.Glu19Asp	missense_variant, splice_region_variant	Exon 2 of 9	1	NM_080860.4	ENSP00000291536.3	Q8WYR4-1
RSPH1	ENST00000493019.1 link	n.117A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 8	2
RSPH1	ENST00000398352.3 link	c.55-214A>T		intron_variant	Intron 1 of 7	5		ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000140

AC:

AN:

250650

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000765

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1460736

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

726702

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.0000898

AC:

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.000932

AC:

AN:

39690

South Asian (SAS)

AF:

0.000313

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000810

AC:

AN:

1111280

Other (OTH)

AF:

0.0000829

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.0000919

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00135

AC:

AN:

5188

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

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:

0.0000847

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000165

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.57A>T (p.E19D) alteration is located in exon 2 (coding exon 2) of the RSPH1 gene. This alteration results from a A to T substitution at nucleotide position 57, causing the glutamic acid (E) at amino acid position 19 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia

Uncertain:1

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 19 of the RSPH1 protein (p.Glu19Asp). This variant is present in population databases (rs200861411, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with RSPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 408127). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.16

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.71

M_CAP

Benign

0.043

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.87

MutationAssessor

Pathogenic

3.1

PhyloP100

-0.71

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.1

REVEL

Benign

0.22

Sift

Uncertain

0.026

Sift4G

Uncertain

0.036

Polyphen

0.058

Vest4

0.68

MutPred

0.24

Gain of loop (P = 0.0502);

MVP

0.061

MPC

0.086

ClinPred

0.080

GERP RS

-10

Varity_R

0.15

gMVP

0.42

Mutation Taster

=74/26

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over