16-31459780-C-T

Variant names:

• chr16-31459780-C-T
• rs587777660
• NM_001105247.2:c.256C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001105247.2(ARMC5):​c.256C>T​(p.Gln86*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,224 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). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ARMC5 NM_001105247.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.528
• Publications: 2 publications found

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

ENSG00000260267 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-31459780-C-T is Pathogenic according to our data. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-31459780-C-T is described in CliVar as Pathogenic. Clinvar id is 144054.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMC5	NM_001105247.2	c.256C>T	p.Gln86*	stop_gained	Exon 1 of 6	ENST00000268314.9	NP_001098717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMC5	ENST00000268314.9	c.256C>T	p.Gln86*	stop_gained	Exon 1 of 6	5	NM_001105247.2	ENSP00000268314.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388224 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 686178

African (AFR) AF: 0.00 AC: 0 AN: 31000

American (AMR) AF: 0.00 AC: 0 AN: 36026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24900

East Asian (EAS) AF: 0.00 AC: 0 AN: 35644

South Asian (SAS) AF: 0.00 AC: 0 AN: 80196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4282

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082070

Other (OTH) AF: 0.00 AC: 0 AN: 57856

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

ACTH-independent macronodular adrenal hyperplasia 2 Pathogenic:1

Nov 28, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.24	N
PhyloP100		0.53
Vest4		0.70
GERP RS		3.5
PromoterAI		-0.0052	Neutral
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs587777660; hg19: chr16-31471101;