rs767650589

Variant names:

• chr2-231206273-T-C
• rs767650589
• NM_001352754.2:c.35T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001352754.2(ARMC9):​c.35T>C​(p.Leu12Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARMC9 NM_001352754.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49
• Publications: 0 publications found

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]

ARMC9 Gene-Disease associations (from GenCC):

• Joubert syndrome 30

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352754.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC9	NM_001352754.2	MANE Select	c.35T>C	p.Leu12Pro	missense	Exon 2 of 25	NP_001339683.2	Q7Z3E5-1
	ARMC9	NM_001271466.4		c.35T>C	p.Leu12Pro	missense	Exon 2 of 25	NP_001258395.2	Q7Z3E5-1
	ARMC9	NM_001291656.2		c.35T>C	p.Leu12Pro	missense	Exon 2 of 21	NP_001278585.2	A0A2Q3DP09

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC9	ENST00000611582.5	TSL:5 MANE Select	c.35T>C	p.Leu12Pro	missense	Exon 2 of 25	ENSP00000484804.1	Q7Z3E5-1
	ARMC9	ENST00000349938.8	TSL:1	c.35T>C	p.Leu12Pro	missense	Exon 2 of 21	ENSP00000258417.5	A0A2Q3DP09
	ARMC9	ENST00000958134.1		c.35T>C	p.Leu12Pro	missense	Exon 2 of 26	ENSP00000628193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.71		Loss of stability (P = 0.011)
MVP		0.63
MPC		1.0
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.87
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs767650589; hg19: chr2-232070986;