NM_001010892.3:c.1990C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001010892.3(RSPH4A):c.1990C>T(p.Pro664Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,978 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 8 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0220

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 11
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RSPH4A links:

LOC124901386 (HGNC:):

LOC124901386 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008825988).

BP6

Variant 6-116632280-C-T is Benign according to our data. Variant chr6-116632280-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 355124.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3 link	c.1990C>T	p.Pro664Ser	missense_variant	Exon 6 of 6	ENST00000229554.10	NP_001010892.1	Q5TD94-1B3KTA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RSPH4A	ENST00000229554.10 link	c.1990C>T	p.Pro664Ser	missense_variant	Exon 6 of 6	1	NM_001010892.3	ENSP00000229554.5	Q5TD94-1
RSPH4A	ENST00000368581.8 link	c.*51C>T		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000357570.4	Q5TD94-3
RSPH4A	ENST00000368580.4 link	c.1249C>T	p.Pro417Ser	missense_variant	Exon 5 of 5	5		ENSP00000357569.4	Q5TD94-2

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

180

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00444

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00156

AC:

392

AN:

251346

AF XY:

0.00163

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.00467

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00328

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00143

AC:

2092

AN:

1460802

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

1018

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33452

American (AMR)

AF:

0.000604

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00398

AC:

104

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000673

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00348

AC:

186

AN:

53418

Middle Eastern (MID)

AF:

0.00378

AC:

AN:

5026

European-Non Finnish (NFE)

AF:

0.00143

AC:

1588

AN:

1111860

Other (OTH)

AF:

0.00171

AC:

103

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

103

206

309

412

515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00118

AC:

180

AN:

152176

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

41510

American (AMR)

AF:

0.00157

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00444

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00142

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00180

AC:

219

EpiCase

AF:

0.00131

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 11

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Oct 06, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RSPH4A-related disorder

Benign:1

Nov 21, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Primary ciliary dyskinesia

Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

T;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

0.022

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Benign

0.16

Sift

Benign

0.12

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.90

P;.

Vest4

0.13

MVP

0.68

MPC

0.21

ClinPred

0.093

GERP RS

5.1

Varity_R

0.23

gMVP

0.45

Mutation Taster

=86/14

polymorphism

(source)

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

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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