6-158977689-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_031924.8(RSPH3):​c.1106G>A​(p.Arg369Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,614,130 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 (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

RSPH3
NM_031924.8 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.698
Variant links:
Genes affected
RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007828236).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000256 (39/152246) while in subpopulation AFR AF= 0.000915 (38/41548). AF 95% confidence interval is 0.000685. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RSPH3NM_031924.8 linkuse as main transcriptc.1106G>A p.Arg369Gln missense_variant 8/8 ENST00000367069.7 NP_114130.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RSPH3ENST00000367069.7 linkuse as main transcriptc.1106G>A p.Arg369Gln missense_variant 8/81 NM_031924.8 ENSP00000356036 P1
RSPH3ENST00000449822.5 linkuse as main transcriptc.818G>A p.Arg273Gln missense_variant 6/62 ENSP00000393195

Frequencies

GnomAD3 genomes
AF:
0.000256
AC:
39
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000917
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000135
AC:
34
AN:
251420
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00166
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461884
Hom.:
0
Cov.:
32
AF XY:
0.0000275
AC XY:
20
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00105
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000256
AC:
39
AN:
152246
Hom.:
0
Cov.:
32
AF XY:
0.000255
AC XY:
19
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.000915
Gnomad4 AMR
AF:
0.00
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:
0.0000977
Hom.:
0
Bravo
AF:
0.000393
ESP6500AA
AF:
0.00227
AC:
10
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000206
AC:
25

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 32 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 08, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 511 of the RSPH3 protein (p.Arg511Gln). This variant is present in population databases (rs150432556, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RSPH3-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
0.066
BayesDel_addAF
Benign
-0.66
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
5.1
DANN
Benign
0.17
DEOGEN2
Benign
0.0021
T;.;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.00057
N
LIST_S2
Benign
0.48
T;T;T
M_CAP
Benign
0.0019
T
MetaRNN
Benign
0.0078
T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-1.0
.;.;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
1.1
N;N;N
REVEL
Benign
0.051
Sift
Benign
1.0
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
.;.;B
Vest4
0.048
MVP
0.030
MPC
0.33
ClinPred
0.0025
T
GERP RS
1.5
Varity_R
0.022
gMVP
0.024

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: rs150432556; hg19: chr6-159398721; COSMIC: COSV51922947; COSMIC: COSV51922947; API