rs6927567

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001010892.3(RSPH4A):c.1667G>A(p.Arg556His) variant causes a missense change. The variant allele was found at a frequency of 0.199 in 1,608,588 control chromosomes in the GnomAD database, including 33,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R556C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.19 ( 2822 hom., cov: 32)

Exomes 𝑓: 0.20 ( 30364 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.84

Publications

26 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022907257).

BP6

Variant 6-116629571-G-A is Benign according to our data. Variant chr6-116629571-G-A is described in ClinVar as Benign. ClinVar VariationId is 165060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010892.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH4A	NM_001010892.3	MANE Select	c.1667G>A	p.Arg556His	missense	Exon 4 of 6	NP_001010892.1
	RSPH4A	NM_001161664.2		c.1663-864G>A		intron	N/A	NP_001155136.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RSPH4A	ENST00000229554.10	TSL:1 MANE Select	c.1667G>A	p.Arg556His	missense	Exon 4 of 6	ENSP00000229554.5
RSPH4A	ENST00000368581.8	TSL:1	c.1663-864G>A		intron	N/A	ENSP00000357570.4
RSPH4A	ENST00000368580.4	TSL:5	c.926G>A	p.Arg309His	missense	Exon 3 of 5	ENSP00000357569.4

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28334

AN:

151838

Hom.:

2819

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.291

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.199

GnomAD2 exomes

AF:

0.214

AC:

53235

AN:

248496

AF XY:

0.214

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.218

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.300

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.222

GnomAD4 exome

AF:

0.200

AC:

291692

AN:

1456632

Hom.:

30364

Cov.:

AF XY:

0.201

AC XY:

145604

AN XY:

724974

show subpopulations

African (AFR)

AF:

0.116

AC:

3861

AN:

33396

American (AMR)

AF:

0.214

AC:

9559

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

6171

AN:

26076

East Asian (EAS)

AF:

0.320

AC:

12686

AN:

39634

South Asian (SAS)

AF:

0.215

AC:

18544

AN:

86118

European-Finnish (FIN)

AF:

0.257

AC:

13688

AN:

53240

Middle Eastern (MID)

AF:

0.198

AC:

1141

AN:

5752

European-Non Finnish (NFE)

AF:

0.193

AC:

213930

AN:

1107472

Other (OTH)

AF:

0.201

AC:

12112

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

11211

22423

33634

44846

56057

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7518

15036

22554

30072

37590

<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:

0.187

AC:

28347

AN:

151956

Hom.:

2822

Cov.:

AF XY:

0.190

AC XY:

14145

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.121

AC:

4994

AN:

41436

American (AMR)

AF:

0.202

AC:

3092

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

819

AN:

3468

East Asian (EAS)

AF:

0.291

AC:

1498

AN:

5150

South Asian (SAS)

AF:

0.216

AC:

1043

AN:

4824

European-Finnish (FIN)

AF:

0.254

AC:

2677

AN:

10524

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.199

AC:

13536

AN:

67958

Other (OTH)

AF:

0.200

AC:

422

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1163

2326

3488

4651

5814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.200

Hom.:

14884

Bravo

AF:

0.179

TwinsUK

AF:

0.198

AC:

736

ALSPAC

AF:

0.197

AC:

758

ESP6500AA

AF:

0.120

AC:

529

ESP6500EA

AF:

0.195

AC:

1679

ExAC

AF:

0.213

AC:

25871

Asia WGS

AF:

0.263

AC:

913

AN:

3478

EpiCase

AF:

0.198

EpiControl

AF:

0.202

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Primary ciliary dyskinesia (2)

not provided (1)

Primary ciliary dyskinesia 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.085

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.84

MutationAssessor

Pathogenic

3.9

PhyloP100

5.8

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.80

Vest4

0.90

MPC

0.70

ClinPred

0.095

GERP RS

5.2

Varity_R

0.77

gMVP

0.73

Mutation Taster

=56/44

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over