Genetic Variant ARMC9:p.Ile180Arg (chr2-231222762-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001352754.2(ARMC9):c.539T>G(p.Ile180Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I180K) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARMC9
NM_001352754.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.35

Publications

21 publications found

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]

ARMC9 Gene-Disease associations (from GenCC):

Joubert syndrome 30
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ARMC9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17690906).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARMC9	NM_001352754.2	MANE Select	c.539T>G	p.Ile180Arg	missense	Exon 6 of 25	NP_001339683.2
ARMC9	NM_001271466.4		c.539T>G	p.Ile180Arg	missense	Exon 6 of 25	NP_001258395.2
ARMC9	NM_001291656.2		c.539T>G	p.Ile180Arg	missense	Exon 6 of 21	NP_001278585.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARMC9	ENST00000611582.5	TSL:5 MANE Select	c.539T>G	p.Ile180Arg	missense	Exon 6 of 25	ENSP00000484804.1
ARMC9	ENST00000349938.8	TSL:1	c.539T>G	p.Ile180Arg	missense	Exon 6 of 21	ENSP00000258417.5
ARMC9	ENST00000683275.1		c.539T>G	p.Ile180Arg	missense	Exon 6 of 22	ENSP00000506823.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1439418

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717186

African (AFR)

AF:

0.00

AC:

AN:

32774

American (AMR)

AF:

0.00

AC:

AN:

43954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25938

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

84786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094096

Other (OTH)

AF:

0.00

AC:

AN:

59506

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.043

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.075

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.78

M_CAP

Benign

0.015

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

7.3

PrimateAI

Benign

0.46

PROVEAN

Benign

1.8

REVEL

Benign

0.14

Sift

Uncertain

0.027

Sift4G

Uncertain

0.058

Polyphen

0.0050

Vest4

0.19

MutPred

0.51

Gain of MoRF binding (P = 0.0165)

MVP

0.29

MPC

0.38

ClinPred

0.90

GERP RS

5.6

Varity_R

0.15

gMVP

0.44

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over