16-31462641-T-C

Position:

• chr16-31462641-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001105247.2(ARMC5):​c.1094T>C​(p.Leu365Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ARMC5 NM_001105247.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant 16-31462641-T-C is Pathogenic according to our data. Variant chr16-31462641-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 144058.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARMC5	NM_001105247.2	c.1094T>C	p.Leu365Pro	missense_variant	3/6	ENST00000268314.9	NP_001098717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARMC5	ENST00000268314.9	c.1094T>C	p.Leu365Pro	missense_variant	3/6	5	NM_001105247.2	ENSP00000268314	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

ACTH-independent macronodular adrenal hyperplasia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T;.;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.3	D;D;D;D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D;D;D;.
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0, 0.99	.;D;D;D;.
Vest4		0.96
MVP		0.56
MPC		1.9
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.82
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs587777663; hg19: chr16-31473962;