2-231222762-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001352754.2(ARMC9):c.539T>A(p.Ile180Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 1 in 152,354 control chromosomes in the GnomAD database, including 76,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I180E) has been classified as Benign.

Frequency

Genomes: 𝑓 1.0 ( 76156 hom., cov: 32)

Exomes 𝑓: 1.0 ( 719505 hom. )

Failed GnomAD Quality Control

Consequence

ARMC9
NM_001352754.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.538906E-7).

BP6

Variant 2-231222762-T-A is Benign according to our data. Variant chr2-231222762-T-A is described in ClinVar as Benign. ClinVar VariationId is 1167999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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>A	p.Ile180Lys	missense	Exon 6 of 25	NP_001339683.2
ARMC9	NM_001271466.4		c.539T>A	p.Ile180Lys	missense	Exon 6 of 25	NP_001258395.2
ARMC9	NM_001291656.2		c.539T>A	p.Ile180Lys	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>A	p.Ile180Lys	missense	Exon 6 of 25	ENSP00000484804.1
ARMC9	ENST00000349938.8	TSL:1	c.539T>A	p.Ile180Lys	missense	Exon 6 of 21	ENSP00000258417.5
ARMC9	ENST00000683275.1		c.539T>A	p.Ile180Lys	missense	Exon 6 of 22	ENSP00000506823.1

Frequencies

GnomAD3 genomes

AF:

1.00

AC:

152215

AN:

152236

Hom.:

76097

Cov.:

show subpopulations

Gnomad AFR

AF:

1.00

Gnomad AMI

AF:

0.993

Gnomad AMR

AF:

1.00

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

1.00

GnomAD2 exomes

AF:

1.00

AC:

247607

AN:

247638

AF XY:

1.00

show subpopulations

Gnomad AFR exome

AF:

1.00

Gnomad AMR exome

AF:

1.00

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

1.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

1.00

AC:

1439215

AN:

1439420

Hom.:

719505

Cov.:

AF XY:

1.00

AC XY:

717093

AN XY:

717186

show subpopulations

African (AFR)

AF:

1.00

AC:

32773

AN:

32774

American (AMR)

AF:

1.00

AC:

43945

AN:

43954

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

25938

AN:

25938

East Asian (EAS)

AF:

1.00

AC:

39528

AN:

39528

South Asian (SAS)

AF:

1.00

AC:

84782

AN:

84786

European-Finnish (FIN)

AF:

1.00

AC:

53336

AN:

53346

Middle Eastern (MID)

AF:

1.00

AC:

5488

AN:

5490

European-Non Finnish (NFE)

AF:

1.00

AC:

1093925

AN:

1094098

Other (OTH)

AF:

1.00

AC:

59500

AN:

59506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21206

42412

63618

84824

106030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

1.00

AC:

152333

AN:

152354

Hom.:

76156

Cov.:

AF XY:

1.00

AC XY:

74486

AN XY:

74500

show subpopulations

African (AFR)

AF:

1.00

AC:

41576

AN:

41576

American (AMR)

AF:

1.00

AC:

15309

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5192

AN:

5192

South Asian (SAS)

AF:

1.00

AC:

4820

AN:

4820

European-Finnish (FIN)

AF:

1.00

AC:

10623

AN:

10624

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68028

AN:

68038

Other (OTH)

AF:

1.00

AC:

2114

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.848

Hom.:

15724

Bravo

AF:

1.00

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

1.00

AC:

4398

ESP6500EA

AF:

1.00

AC:

8591

ExAC

AF:

1.00

AC:

121375

Asia WGS

AF:

1.00

AC:

3478

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.043

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.61

MetaRNN

Benign

5.5e-7

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

PhyloP100

7.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

2.8

REVEL

Benign

0.14

Sift

Benign

0.12

Sift4G

Benign

0.29

Polyphen

0.0

Vest4

0.11

MPC

0.38

ClinPred

0.046

GERP RS

5.6

Varity_R

0.096

gMVP

0.50

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over