rs759799287

chr2-231262306-C-Achr2-231262306-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001352754.2(ARMC9):c.1027C>A(p.Arg343Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000274 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R343C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARMC9 NM_001352754.2 missense, splice_region
• Scores: Splicing: ADA: 0.5027
• Clinical Significance: Uncertain significance criteria provided, single submitter P:3 U:1
• Conservation: PhyloP100: 3.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-231262306-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMC9	NM_001352754.2	c.1027C>A	p.Arg343Ser	missense_variant, splice_region_variant	12/25	ENST00000611582.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMC9	ENST00000611582.5	c.1027C>A	p.Arg343Ser	missense_variant, splice_region_variant	12/25	5	NM_001352754.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135908

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461796 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727202

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 30 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 12, 2024	The heterozygous p.Arg343Ser variant in ARMC9 was identified by our study in one individual with congenital fibrosis of the extraocular muscles and Joubert syndrome, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Arg343Ser variant in ARMC9 has been previously reported in two siblings with Joubert syndrome 30 (PMID: 28625504) but has been identified in 0.0009% (1/113742) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs759799287). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These two affected individuals were compound heterozygotes that carried a likely pathogenic variant in trans (ClinVar Variation ID: 427933), which increases the likelihood that the p.Arg343Ser variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 427937) and has been interpreted as pathogenic by OMIM and the UW Hindbrain Malformation Research Program and as likely pathogenic by the University of Washington Center for Mendelian Genomics. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg343Cys, has been reported in association with disease in the literature and in ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 28625504, 31474318, 32552793, 35186037; Variation ID: 427932). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3, PM5_Supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 16, 2017	- -

ARMC9-related Joubert syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

UW Hindbrain Malformation Research Program, University of Washington

May 01, 2017

- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D;.;.;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.94
MVP		0.54
MPC		0.87
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
dbscSNV1_RF	Benign	0.69
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

Other links and lift over

dbSNP: rs759799287; hg19: chr2-232127019;