chr21-42472841-T-C

Position:

chr21-42472841-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_080860.4(RSPH1):c.907A>G(p.Arg303Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,609,748 control chromosomes in the GnomAD database, including 7 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 7 hom. )

Consequence

RSPH1
NM_080860.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.46

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006163895).

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RSPH1	NM_080860.4 linkuse as main transcript	c.907A>G	p.Arg303Gly	missense_variant	9/9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2 linkuse as main transcript	c.793A>G	p.Arg265Gly	missense_variant	8/8		NP_001273435.1
RSPH1	XM_011529786.2 linkuse as main transcript	c.835A>G	p.Arg279Gly	missense_variant	8/8		XP_011528088.1
RSPH1	XM_005261208.3 linkuse as main transcript	c.700A>G	p.Arg234Gly	missense_variant	7/7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8 linkuse as main transcript	c.907A>G	p.Arg303Gly	missense_variant	9/9	1	NM_080860.4	ENSP00000291536	P1	Q8WYR4-1
RSPH1	ENST00000398352.3 linkuse as main transcript	c.793A>G	p.Arg265Gly	missense_variant	8/8	5		ENSP00000381395		Q8WYR4-2
RSPH1	ENST00000493019.1 linkuse as main transcript	n.2525A>G		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000872

AC:

219

AN:

251104

Hom.:

AF XY:

0.000943

AC XY:

128

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00207

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00118

AC:

1719

AN:

1457382

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

866

AN XY:

725382

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.0000896

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00218

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.00131

Gnomad4 OTH exome

AF:

0.000764

GnomAD4 genome

AF:

0.000774

AC:

118

AN:

152366

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000506

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00103

AC:

125

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000873

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.907A>G (p.R303G) alteration is located in exon 9 (coding exon 9) of the RSPH1 gene. This alteration results from a A to G substitution at nucleotide position 907, causing the arginine (R) at amino acid position 303 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia 24

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 11, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

RSPH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 18, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.048

T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0062

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.76

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.90

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.039

D;D

Polyphen

0.61

P;.

Vest4

0.20

MVP

0.31

MPC

0.17

ClinPred

0.033

GERP RS

3.0

Varity_R

0.14

gMVP

0.12

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

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