rs753432312

Variant names:

• chr2-231276637-C-T
• rs753432312
• NM_001352754.2:c.1336C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001352754.2(ARMC9):​c.1336C>T​(p.Arg446Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R446H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ARMC9 NM_001352754.2 missense, splice_region
• Scores: Splicing: ADA: 0.9657
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 3.44
• Publications: 1 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-231276637-C-T is Pathogenic according to our data. Variant chr2-231276637-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 427939.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1336C>T	p.Arg446Cys	missense splice_region	Exon 15 of 25	NP_001339683.2	Q7Z3E5-1
	ARMC9	NM_001271466.4		c.1336C>T	p.Arg446Cys	missense splice_region	Exon 15 of 25	NP_001258395.2	Q7Z3E5-1
	ARMC9	NM_001291656.2		c.1336C>T	p.Arg446Cys	missense splice_region	Exon 15 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.1336C>T	p.Arg446Cys	missense splice_region	Exon 15 of 25	ENSP00000484804.1	Q7Z3E5-1
	ARMC9	ENST00000349938.8	TSL:1	c.1336C>T	p.Arg446Cys	missense splice_region	Exon 15 of 21	ENSP00000258417.5	A0A2Q3DP09
	ARMC9	ENST00000958134.1		c.1336C>T	p.Arg446Cys	missense splice_region	Exon 15 of 26	ENSP00000628193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251320 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461802 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	ARMC9-related Joubert syndrome (1)
1	-	-	Joubert syndrome (1)
1	-	-	Joubert syndrome 30 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.37		Loss of solvent accessibility (P = 0.0404)
MVP		0.74
MPC		0.96
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.52
gMVP		0.52
Mutation Taster		=52/48	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.80
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: rs753432312; hg19: chr2-232141350; COSMIC: COSV106107822;