chr6-116622812-G-A

Position:

chr6-116622812-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001010892.3(RSPH4A):c.731G>A(p.Arg244His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,611,804 control chromosomes in the GnomAD database, including 432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 36 hom., cov: 33)

Exomes 𝑓: 0.020 ( 396 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.96

Variant links:

Genes affected

RSPH4A (HGNC:21558): (radial spoke head component 4A) This gene encodes a protein that appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein. Mutations in this gene cause primary ciliary dyskinesia 1, a disease arising from dysmotility of motile cilia and sperm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

RSPH4A links:

RSPH4A (HGNC:):

RSPH4A 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=0.0094536245).

BP6

Variant 6-116622812-G-A is Benign according to our data. Variant chr6-116622812-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 165059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2465/152224) while in subpopulation NFE AF= 0.0227 (1545/68014). AF 95% confidence interval is 0.0218. There are 36 homozygotes in gnomad4. There are 1155 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3 linkuse as main transcript	c.731G>A	p.Arg244His	missense_variant	2/6	ENST00000229554.10	NP_001010892.1	Q5TD94-1B3KTA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RSPH4A	ENST00000229554.10 linkuse as main transcript	c.731G>A	p.Arg244His	missense_variant	2/6	1	NM_001010892.3	ENSP00000229554.5	Q5TD94-1
RSPH4A	ENST00000368581.8 linkuse as main transcript	c.731G>A	p.Arg244His	missense_variant	2/5	1		ENSP00000357570.4	Q5TD94-3
RSPH4A	ENST00000368580.4 linkuse as main transcript	c.731G>A	p.Arg244His	missense_variant	2/5	5		ENSP00000357569.4	Q5TD94-2

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2459

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0222

Gnomad FIN

AF:

0.00999

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0227

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0200

AC:

5012

AN:

250896

Hom.:

AF XY:

0.0209

AC XY:

2837

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.0221

Gnomad ASJ exome

AF:

0.0521

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.0227

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0205

AC:

29901

AN:

1459580

Hom.:

396

Cov.:

AF XY:

0.0209

AC XY:

15188

AN XY:

726246

show subpopulations

Gnomad4 AFR exome

AF:

0.00299

Gnomad4 AMR exome

AF:

0.0222

Gnomad4 ASJ exome

AF:

0.0486

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0224

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.0212

Gnomad4 OTH exome

AF:

0.0222

GnomAD4 genome

AF:

0.0162

AC:

2465

AN:

152224

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1155

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00364

Gnomad4 AMR

AF:

0.0204

Gnomad4 ASJ

AF:

0.0513

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0224

Gnomad4 FIN

AF:

0.00999

Gnomad4 NFE

AF:

0.0227

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0226

Hom.:

Bravo

AF:

0.0164

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0233

AC:

200

ExAC

AF:

0.0195

AC:

2367

Asia WGS

AF:

0.00751

AC:

AN:

3476

EpiCase

AF:

0.0261

EpiControl

AF:

0.0271

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	This variant is associated with the following publications: (PMID: 31213628) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RSPH4A: BP4, BS1, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg244His in exon 2 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 2.3% (200/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41289942). -

Primary ciliary dyskinesia 11

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 12, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

.;T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.0095

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

M;M;M

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.021

D;D;D

Polyphen

0.87

P;B;.

Vest4

0.17

MPC

0.29

ClinPred

0.039

GERP RS

4.8

Varity_R

0.52

gMVP

0.35

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