rs117385282

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RSPH1	NM_080860.4 linkuse as main transcript	c.742G>A	p.Gly248Arg	missense_variant	8/9	ENST00000291536.8
RSPH1	NM_001286506.2 linkuse as main transcript	c.628G>A	p.Gly210Arg	missense_variant	7/8
RSPH1	XM_011529786.2 linkuse as main transcript	c.670G>A	p.Gly224Arg	missense_variant	7/8
RSPH1	XM_005261208.3 linkuse as main transcript	c.535G>A	p.Gly179Arg	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8 linkuse as main transcript	c.742G>A	p.Gly248Arg	missense_variant	8/9	1	NM_080860.4	P1	Q8WYR4-1
RSPH1	ENST00000398352.3 linkuse as main transcript	c.628G>A	p.Gly210Arg	missense_variant	7/8	5			Q8WYR4-2
RSPH1	ENST00000493019.1 linkuse as main transcript	n.2360G>A		non_coding_transcript_exon_variant	7/8	2

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

GnomAD3 exomes

AF:

0.155

AC:

39048

AN:

251262

Hom.:

3492

AF XY:

0.159

AC XY:

21619

AN XY:

135818

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 SAS exome

AF:

0.151

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

Gnomad4 AFR exome

AF:

0.0293

Gnomad4 AMR exome

AF:

0.159

Gnomad4 ASJ exome

AF:

0.181

Gnomad4 EAS exome

AF:

0.00846

Gnomad4 SAS exome

AF:

0.153

Gnomad4 FIN exome

AF:

0.158

Gnomad4 NFE exome

AF:

0.202

Gnomad4 OTH exome

AF:

0.167

GnomAD4 genome

AF:

0.132

AC:

20059

AN:

151684

Hom.:

1777

Cov.:

AF XY:

0.130

AC XY:

9622

AN XY:

74102

show subpopulations

Gnomad4 AFR

AF:

0.0347

Gnomad4 AMR

AF:

0.135

Gnomad4 ASJ

AF:

0.192

Gnomad4 EAS

AF:

0.00767

Gnomad4 SAS

AF:

0.152

Gnomad4 FIN

AF:

0.151

Gnomad4 NFE

AF:

0.191

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.178

Hom.:

3999

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Gly248Arg in exon 8 of RSPH1: This variant is not expected to have clinical sign ificance because it has been identified in 19.2% (1647/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs117385282). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -

Primary ciliary dyskinesia 24

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.38

DEOGEN2

Benign

0.056

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.00077

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.077

Sift

Benign

0.53

T;T

Sift4G

Benign

0.092

T;D

Polyphen

0.0030

B;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over