6-116616669-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001010892.3(RSPH4A):ā€‹c.46G>Cā€‹(p.Glu16Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

RSPH4A
NM_001010892.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.20
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.053227723).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RSPH4ANM_001010892.3 linkuse as main transcriptc.46G>C p.Glu16Gln missense_variant 1/6 ENST00000229554.10 NP_001010892.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RSPH4AENST00000229554.10 linkuse as main transcriptc.46G>C p.Glu16Gln missense_variant 1/61 NM_001010892.3 ENSP00000229554 P1Q5TD94-1
RSPH4AENST00000368581.8 linkuse as main transcriptc.46G>C p.Glu16Gln missense_variant 1/51 ENSP00000357570 Q5TD94-3
RSPH4AENST00000368580.4 linkuse as main transcriptc.46G>C p.Glu16Gln missense_variant 1/55 ENSP00000357569 Q5TD94-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152112
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
251080
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135754
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461860
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
10
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152112
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 07, 2015The p.E16Q variant (also known as c.46G>C), located in coding exon 1 of the RSPH4A gene, results from a G to C substitution at nucleotide position 46. The glutamic acid at codon 16 is replaced by glutamine, an amino acid with some highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 05, 2022This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 16 of the RSPH4A protein (p.Glu16Gln). This variant is present in population databases (rs780975506, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RSPH4A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
15
DANN
Benign
0.58
DEOGEN2
Benign
0.0011
.;T;.
Eigen
Benign
-0.87
Eigen_PC
Benign
-0.91
FATHMM_MKL
Benign
0.093
N
LIST_S2
Benign
0.53
T;T;T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.053
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.070
N;N;N
REVEL
Benign
0.053
Sift
Benign
0.19
T;T;T
Sift4G
Benign
0.63
T;T;T
Polyphen
0.90
P;P;.
Vest4
0.087
MutPred
0.12
Gain of MoRF binding (P = 0.056);Gain of MoRF binding (P = 0.056);Gain of MoRF binding (P = 0.056);
MVP
0.61
MPC
0.17
ClinPred
0.092
T
GERP RS
1.8
Varity_R
0.060
gMVP
0.15

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.

Other links and lift over

dbSNP: rs780975506; hg19: chr6-116937832; API