chr16-31466773-C-T

Variant names:

• chr16-31466773-C-T
• rs587777659
• NM_001105247.2:c.2692C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP3_Moderate PP5 BS2

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.316
• Publications: 8 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Cushing syndrome due to macronodular adrenal hyperplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105247.2. 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
	ARMC5	NM_001105247.2	MANE Select	c.2692C>T	p.Arg898Trp	missense	Exon 6 of 6	NP_001098717.1	Q96C12-1
	ARMC5	NM_001288767.2		c.2977C>T	p.Arg993Trp	missense	Exon 8 of 8	NP_001275696.1	J3KQ26
	ARMC5	NM_001301820.1		c.2788C>T	p.Arg930Trp	missense	Exon 7 of 7	NP_001288749.1	Q96C12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC5	ENST00000268314.9	TSL:5 MANE Select	c.2692C>T	p.Arg898Trp	missense	Exon 6 of 6	ENSP00000268314.4	Q96C12-1
	ARMC5	ENST00000457010.6	TSL:1	c.*1572C>T		3_prime_UTR	Exon 4 of 4	ENSP00000399561.2	Q96C12-4
	ARMC5	ENST00000408912.7	TSL:2	c.2977C>T	p.Arg993Trp	missense	Exon 8 of 8	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000972 AC: 2 AN: 205732 AF XY: 0.00000898

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: 9 AN: 1425022 Hom.: 0 Cov.: 30 AF XY: 0.00000708 AC XY: 5 AN XY: 705854

African (AFR) AF: 0.00 AC: 0 AN: 32422

American (AMR) AF: 0.00 AC: 0 AN: 38664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23416

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79752

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5432

European-Non Finnish (NFE) AF: 0.00000548 AC: 6 AN: 1095448

Other (OTH) AF: 0.0000170 AC: 1 AN: 58696

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	ACTH-independent macronodular adrenal hyperplasia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.32
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.60
MPC		1.5
ClinPred		0.57	D
GERP RS		3.1
Varity_R		0.15
gMVP		0.71
Mutation Taster		=12/88	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: rs587777659; hg19: chr16-31478094;