rs780265931
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_001352754.2(ARMC9):c.1474G>A(p.Gly492Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000124 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ARMC9
NM_001352754.2 missense, splice_region
NM_001352754.2 missense, splice_region
Scores
6
10
3
Splicing: ADA: 1.000
1
Clinical Significance
Conservation
PhyloP100: 4.43
Genes affected
ARMC9 (HGNC:20730): (armadillo repeat containing 9) Predicted to be involved in cilium assembly and positive regulation of smoothened signaling pathway. Located in centriole and ciliary basal body. Implicated in Joubert syndrome 30. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-231276775-G-A is Pathogenic according to our data. Variant chr2-231276775-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427935.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-231276775-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ARMC9 | NM_001352754.2 | c.1474G>A | p.Gly492Arg | missense_variant, splice_region_variant | 15/25 | ENST00000611582.5 | NP_001339683.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ARMC9 | ENST00000611582.5 | c.1474G>A | p.Gly492Arg | missense_variant, splice_region_variant | 15/25 | 5 | NM_001352754.2 | ENSP00000484804.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251010Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135634
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461656Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727124
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
ARMC9-related Joubert syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | research | UW Hindbrain Malformation Research Program, University of Washington | May 01, 2017 | - - |
Joubert syndrome 30 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 16, 2017 | - - |
Dandy-Walker syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 07, 2022 | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 427935). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 492 of the ARMC9 protein (p.Gly492Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 28625504). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. - |
Familial aplasia of the vermis Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;D;D;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;.;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D
REVEL
Uncertain
Sift
Pathogenic
D;.;.;D
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at