rs780265931

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

Scores

6
10
3
Splicing: ADA: 1.000
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:5

Conservation

PhyloP100: 4.43
Variant links:
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]

Genome browser will be placed here

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
ARMC9NM_001352754.2 linkuse as main transcriptc.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
ARMC9ENST00000611582.5 linkuse as main transcriptc.1474G>A p.Gly492Arg missense_variant, splice_region_variant 15/255 NM_001352754.2 ENSP00000484804.1 Q7Z3E5-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00000398
AC:
1
AN:
251010
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135634
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461656
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
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
ExAC
AF:
0.00000824
AC:
1

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 providedresearchUW Hindbrain Malformation Research Program, University of WashingtonMay 01, 2017- -
Joubert syndrome 30 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 16, 2017- -
Dandy-Walker syndrome Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 07, 2022Algorithms 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 providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
.;D;D;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;.;D
M_CAP
Benign
0.063
D
MetaRNN
Uncertain
0.73
D;D;D;D
MetaSVM
Benign
-0.44
T
MutationAssessor
Uncertain
2.7
.;M;M;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-6.1
D;.;.;D
REVEL
Uncertain
0.37
Sift
Pathogenic
0.0
D;.;.;D
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.54
MutPred
0.40
Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);Gain of solvent accessibility (P = 0.006);.;
MVP
0.82
MPC
0.90
ClinPred
0.99
D
GERP RS
4.2
Varity_R
0.45
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
SpliceAI score (max)
0.95
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.95
Position offset: 0

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: rs780265931; hg19: chr2-232141488; API