NM_001010892.3:c.1879A>C

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.1879A>C​(p.Asn627His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,606,826 control chromosomes in the GnomAD database, including 6,293 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. N627K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.11 ( 1643 hom., cov: 31)
Exomes 𝑓: 0.062 ( 4650 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

3
6
8

Clinical Significance

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

Conservation

PhyloP100: 7.22

Publications

21 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=0.002024293).
BP6
Variant 6-116630515-A-C is Benign according to our data. Variant chr6-116630515-A-C is described in ClinVar as [Benign]. Clinvar id is 165062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RSPH4ANM_001010892.3 linkc.1879A>C p.Asn627His missense_variant Exon 5 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.1879A>C p.Asn627His missense_variant Exon 5 of 6 1 NM_001010892.3 ENSP00000229554.5 Q5TD94-1
RSPH4AENST00000368581.8 linkc.1743A>C p.Pro581Pro synonymous_variant Exon 4 of 5 1 ENSP00000357570.4 Q5TD94-3
RSPH4AENST00000368580.4 linkc.1138A>C p.Asn380His missense_variant Exon 4 of 5 5 ENSP00000357569.4 Q5TD94-2

Frequencies

GnomAD3 genomes
AF:
0.113
AC:
17162
AN:
151826
Hom.:
1633
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.243
Gnomad AMI
AF:
0.00548
Gnomad AMR
AF:
0.167
Gnomad ASJ
AF:
0.0709
Gnomad EAS
AF:
0.0224
Gnomad SAS
AF:
0.119
Gnomad FIN
AF:
0.0301
Gnomad MID
AF:
0.0570
Gnomad NFE
AF:
0.0457
Gnomad OTH
AF:
0.0992
GnomAD2 exomes
AF:
0.0925
AC:
23267
AN:
251438
AF XY:
0.0857
show subpopulations
Gnomad AFR exome
AF:
0.246
Gnomad AMR exome
AF:
0.238
Gnomad ASJ exome
AF:
0.0659
Gnomad EAS exome
AF:
0.0192
Gnomad FIN exome
AF:
0.0303
Gnomad NFE exome
AF:
0.0463
Gnomad OTH exome
AF:
0.0766
GnomAD4 exome
AF:
0.0621
AC:
90341
AN:
1454882
Hom.:
4650
Cov.:
29
AF XY:
0.0623
AC XY:
45124
AN XY:
724174
show subpopulations
African (AFR)
AF:
0.251
AC:
8342
AN:
33228
American (AMR)
AF:
0.233
AC:
10435
AN:
44700
Ashkenazi Jewish (ASJ)
AF:
0.0706
AC:
1843
AN:
26088
East Asian (EAS)
AF:
0.0241
AC:
957
AN:
39652
South Asian (SAS)
AF:
0.115
AC:
9894
AN:
86074
European-Finnish (FIN)
AF:
0.0305
AC:
1629
AN:
53414
Middle Eastern (MID)
AF:
0.0469
AC:
270
AN:
5754
European-Non Finnish (NFE)
AF:
0.0477
AC:
52701
AN:
1105816
Other (OTH)
AF:
0.0710
AC:
4270
AN:
60156
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
4079
8157
12236
16314
20393
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2306
4612
6918
9224
11530
<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:
0.113
AC:
17202
AN:
151944
Hom.:
1643
Cov.:
31
AF XY:
0.112
AC XY:
8332
AN XY:
74276
show subpopulations
African (AFR)
AF:
0.243
AC:
10062
AN:
41378
American (AMR)
AF:
0.167
AC:
2552
AN:
15246
Ashkenazi Jewish (ASJ)
AF:
0.0709
AC:
246
AN:
3470
East Asian (EAS)
AF:
0.0225
AC:
116
AN:
5166
South Asian (SAS)
AF:
0.120
AC:
576
AN:
4818
European-Finnish (FIN)
AF:
0.0301
AC:
318
AN:
10570
Middle Eastern (MID)
AF:
0.0510
AC:
15
AN:
294
European-Non Finnish (NFE)
AF:
0.0457
AC:
3105
AN:
67982
Other (OTH)
AF:
0.0982
AC:
207
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
698
1396
2094
2792
3490
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
178
356
534
712
890
<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:
0.0688
Hom.:
3329
Bravo
AF:
0.131
TwinsUK
AF:
0.0572
AC:
212
ALSPAC
AF:
0.0535
AC:
206
ESP6500AA
AF:
0.227
AC:
999
ESP6500EA
AF:
0.0521
AC:
448
ExAC
AF:
0.0901
AC:
10933
Asia WGS
AF:
0.0860
AC:
301
AN:
3478
EpiCase
AF:
0.0463
EpiControl
AF:
0.0487

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

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

Asn627His in exon 5 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 22.7% (999/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs9488991). -

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

- -

Primary ciliary dyskinesia Benign:2
Dec 24, 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. -

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

- -

Primary ciliary dyskinesia 11 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: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 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
Feb 25, 2019
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.39
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.071
T;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.79
T;T
MetaRNN
Benign
0.0020
T;T
MetaSVM
Benign
-1.1
T
PhyloP100
7.2
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-4.6
D;D
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;.
Vest4
0.44
MPC
0.63
ClinPred
0.030
T
GERP RS
5.5
Varity_R
0.77
gMVP
0.79
Mutation Taster
=82/18
polymorphism (auto)

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

Other links and lift over

dbSNP: rs9488991; hg19: chr6-116951678; COSMIC: COSV57634372; API