Genetic Variant ARMC5:p.Arg898Trp (chr16-31466773-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP3_ModeratePP5BS2

The NM_001105247.2(ARMC5):c.2692C>T(p.Arg898Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000632 in 1,425,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

ARMC5
NM_001105247.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.316

Publications

8 publications found

Variant links:

Genes affected

ARMC5 (HGNC:25781): (armadillo repeat containing 5) This gene encodes a member of the ARM (armadillo/beta-catenin-like repeat) superfamily. The ARM repeat is a tandemly repeated sequence motif with approximately 40 amino acid long. This repeat is implicated in mediating protein-protein interactions. The encoded protein contains seven ARM repeats. Mutations in this gene are associated with primary bilateral macronodular adrenal hyperplasia, which is also known as ACTH-independent macronodular adrenal hyperplasia 2. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

ARMC5 Gene-Disease associations (from GenCC):

ACTH-independent macronodular adrenal hyperplasia 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Cushing syndrome due to macronodular adrenal hyperplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARMC5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

PP5

Variant 16-31466773-C-T is Pathogenic according to our data. Variant chr16-31466773-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 144053.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMC5	NM_001105247.2 link	c.2692C>T	p.Arg898Trp	missense_variant	Exon 6 of 6	ENST00000268314.9	NP_001098717.1	Q96C12-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMC5	ENST00000268314.9 link	c.2692C>T	p.Arg898Trp	missense_variant	Exon 6 of 6	5	NM_001105247.2	ENSP00000268314.4		Q96C12-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000972

AC:

AN:

205732

AF XY:

0.00000898

show subpopulations

Gnomad AFR exome

AF:

0.0000722

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:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000632

AC:

AN:

1425022

Hom.:

Cov.:

AF XY:

0.00000708

AC XY:

AN XY:

705854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32422

American (AMR)

AF:

0.00

AC:

AN:

38664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23416

East Asian (EAS)

AF:

0.00

AC:

AN:

39348

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79752

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51844

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5432

European-Non Finnish (NFE)

AF:

0.00000548

AC:

AN:

1095448

Other (OTH)

AF:

0.0000170

AC:

AN:

58696

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

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ACTH-independent macronodular adrenal hyperplasia 2

Pathogenic:1

Jun 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.027

T;T;T;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

D;.;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.69

.;N;N;.

PhyloP100

0.32

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.9

N;N;N;.

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.84

MVP

0.60

MPC

1.5

ClinPred

0.57

GERP RS

3.1

Varity_R

0.15

gMVP

0.71

Mutation Taster

=12/88

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over