6-116617069-C-G

Position:

chr6-116617069-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001010892.3(RSPH4A):c.446C>G(p.Thr149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,614,118 control chromosomes in the GnomAD database, including 10,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 662 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9472 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.617

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:

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=0.0016322434).

BP6

Variant 6-116617069-C-G is Benign according to our data. Variant chr6-116617069-C-G is described in ClinVar as [Benign]. Clinvar id is 178799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116617069-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3 linkuse as main transcript	c.446C>G	p.Thr149Ser	missense_variant	1/6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10 linkuse as main transcript	c.446C>G	p.Thr149Ser	missense_variant	1/6	1	NM_001010892.3	ENSP00000229554	P1	Q5TD94-1
RSPH4A	ENST00000368581.8 linkuse as main transcript	c.446C>G	p.Thr149Ser	missense_variant	1/5	1		ENSP00000357570		Q5TD94-3
RSPH4A	ENST00000368580.4 linkuse as main transcript	c.446C>G	p.Thr149Ser	missense_variant	1/5	5		ENSP00000357569		Q5TD94-2

Frequencies

GnomAD3 genomes

AF:

0.0784

AC:

11923

AN:

152150

Hom.:

662

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.125

Gnomad AMR

AF:

0.0676

Gnomad ASJ

AF:

0.0778

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0234

Gnomad FIN

AF:

0.0776

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.124

Gnomad OTH

AF:

0.0837

GnomAD3 exomes

AF:

0.0803

AC:

20182

AN:

251352

Hom.:

1068

AF XY:

0.0812

AC XY:

11029

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.0199

Gnomad AMR exome

AF:

0.0517

Gnomad ASJ exome

AF:

0.0788

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0324

Gnomad FIN exome

AF:

0.0846

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.0940

GnomAD4 exome

AF:

0.108

AC:

157392

AN:

1461850

Hom.:

9472

Cov.:

AF XY:

0.106

AC XY:

76816

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0172

Gnomad4 AMR exome

AF:

0.0553

Gnomad4 ASJ exome

AF:

0.0761

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.0325

Gnomad4 FIN exome

AF:

0.0907

Gnomad4 NFE exome

AF:

0.124

Gnomad4 OTH exome

AF:

0.0966

GnomAD4 genome

AF:

0.0783

AC:

11921

AN:

152268

Hom.:

662

Cov.:

AF XY:

0.0743

AC XY:

5533

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0217

Gnomad4 AMR

AF:

0.0675

Gnomad4 ASJ

AF:

0.0778

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.0232

Gnomad4 FIN

AF:

0.0776

Gnomad4 NFE

AF:

0.125

Gnomad4 OTH

AF:

0.0829

Alfa

AF:

0.107

Hom.:

316

Bravo

AF:

0.0755

TwinsUK

AF:

0.116

AC:

430

ALSPAC

AF:

0.130

AC:

501

ESP6500AA

AF:

0.0268

AC:

118

ESP6500EA

AF:

0.123

AC:

1056

ExAC

AF:

0.0814

AC:

9886

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.118

EpiControl

AF:

0.120

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr149Ser in exon 1 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 12.3% (1056/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs13213314). -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 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. -

Primary ciliary dyskinesia 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.24

DANN

Benign

0.46

DEOGEN2

Benign

0.0050

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.30

T;T;T

MetaRNN

Benign

0.0016

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.60

N;N;N

REVEL

Benign

0.032

Sift

Benign

0.086

T;T;T

Sift4G

Benign

0.33

T;T;T

Polyphen

0.0040

B;B;.

Vest4

0.043

MutPred

0.042

Gain of phosphorylation at T149 (P = 0.0892);Gain of phosphorylation at T149 (P = 0.0892);Gain of phosphorylation at T149 (P = 0.0892);

MPC

0.13

ClinPred

0.0028

GERP RS

2.8

Varity_R

0.035

gMVP

0.065

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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