chr6-116622812-G-A

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R244C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.016 ( 36 hom., cov: 33)
Exomes 𝑓: 0.020 ( 396 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

1
9
8

Clinical Significance

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

Conservation

PhyloP100: 1.96

Publications

14 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

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=0.0094536245).
BP6
Variant 6-116622812-G-A is Benign according to our data. Variant chr6-116622812-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 36 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RSPH4ANM_001010892.3 linkc.731G>A p.Arg244His missense_variant Exon 2 of 6 ENST00000229554.10 NP_001010892.1 Q5TD94-1B3KTA9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RSPH4AENST00000229554.10 linkc.731G>A p.Arg244His missense_variant Exon 2 of 6 1 NM_001010892.3 ENSP00000229554.5 Q5TD94-1
RSPH4AENST00000368581.8 linkc.731G>A p.Arg244His missense_variant Exon 2 of 5 1 ENSP00000357570.4 Q5TD94-3
RSPH4AENST00000368580.4 linkc.731G>A p.Arg244His missense_variant Exon 2 of 5 5 ENSP00000357569.4 Q5TD94-2

Frequencies

GnomAD3 genomes
AF:
0.0162
AC:
2459
AN:
152106
Hom.:
34
Cov.:
33
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
GnomAD2 exomes
AF:
0.0200
AC:
5012
AN:
250896
AF XY:
0.0209
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 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.:
30
AF XY:
0.0209
AC XY:
15188
AN XY:
726246
show subpopulations
African (AFR)
AF:
0.00299
AC:
100
AN:
33448
American (AMR)
AF:
0.0222
AC:
995
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.0486
AC:
1268
AN:
26108
East Asian (EAS)
AF:
0.000177
AC:
7
AN:
39650
South Asian (SAS)
AF:
0.0224
AC:
1933
AN:
86206
European-Finnish (FIN)
AF:
0.0103
AC:
548
AN:
53382
Middle Eastern (MID)
AF:
0.0341
AC:
196
AN:
5752
European-Non Finnish (NFE)
AF:
0.0212
AC:
23518
AN:
1110008
Other (OTH)
AF:
0.0222
AC:
1336
AN:
60306
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.455
Heterozygous variant carriers
0
1282
2564
3846
5128
6410
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
886
1772
2658
3544
4430
<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:
0.0162
AC:
2465
AN:
152224
Hom.:
36
Cov.:
33
AF XY:
0.0155
AC XY:
1155
AN XY:
74440
show subpopulations
African (AFR)
AF:
0.00364
AC:
151
AN:
41520
American (AMR)
AF:
0.0204
AC:
312
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.0513
AC:
178
AN:
3472
East Asian (EAS)
AF:
0.000578
AC:
3
AN:
5190
South Asian (SAS)
AF:
0.0224
AC:
108
AN:
4820
European-Finnish (FIN)
AF:
0.00999
AC:
106
AN:
10608
Middle Eastern (MID)
AF:
0.0340
AC:
10
AN:
294
European-Non Finnish (NFE)
AF:
0.0227
AC:
1545
AN:
68014
Other (OTH)
AF:
0.0208
AC:
44
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
124
248
373
497
621
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
30
60
90
120
150
<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:
0.0208
Hom.:
148
Bravo
AF:
0.0164
TwinsUK
AF:
0.0227
AC:
84
ALSPAC
AF:
0.0218
AC:
84
ESP6500AA
AF:
0.00431
AC:
19
ESP6500EA
AF:
0.0233
AC:
200
ExAC
AF:
0.0195
AC:
2367
Asia WGS
AF:
0.00751
AC:
26
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
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jun 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

RSPH4A: BP4, BS1, BS2 -

Feb 11, 2020
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31213628) -

not specified Benign:2
Feb 21, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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). -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Primary ciliary dyskinesia 11 Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
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 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. -

Nov 28, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Primary ciliary dyskinesia Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 12, 2014
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.020
.;T;.
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.94
D;D;D
MetaRNN
Benign
0.0095
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Pathogenic
3.0
M;M;M
PhyloP100
2.0
PrimateAI
Benign
0.29
T
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
T
GERP RS
4.8
Varity_R
0.52
gMVP
0.35
Mutation Taster
=66/34
polymorphism (auto)

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

Other links and lift over

dbSNP: rs41289942; hg19: chr6-116943975; COSMIC: COSV57634674; API