16-31459688-C-T

Position:

• chr16-31459688-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001105247.2(ARMC5):​c.164C>T​(p.Ala55Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,418,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARMC5 NM_001105247.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.94

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]

ENSG00000260267 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14815292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARMC5	NM_001105247.2	c.164C>T	p.Ala55Val	missense_variant	1/6	ENST00000268314.9	NP_001098717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARMC5	ENST00000268314.9	c.164C>T	p.Ala55Val	missense_variant	1/6	5	NM_001105247.2	ENSP00000268314.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1418546 Hom.: 0 Cov.: 34 AF XY: 0.00000142 AC XY: 1 AN XY: 705760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000254 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.164C>T (p.A55V) alteration is located in exon 1 (coding exon 1) of the ARMC5 gene. This alteration results from a C to T substitution at nucleotide position 164, causing the alanine (A) at amino acid position 55 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ARMC5-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 30, 2022

The ARMC5 c.449C>T variant is predicted to result in the amino acid substitution p.Ala150Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-31471009-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;.;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.81	T;T;.;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	.;L;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.068
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.94, 0.68	.;P;P;P
Vest4		0.45
MVP		0.56
MPC		0.55
ClinPred		0.79	D
GERP RS		3.3
Varity_R		0.077
gMVP		0.22

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: rs754286092; hg19: chr16-31471009;