10-22959491-T-A

Variant summary

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

The NM_173081.5(ARMC3):c.454T>A(p.Leu152Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARMC3 NM_173081.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.271

Genes affected

ARMC3 (HGNC:30964): (armadillo repeat containing 3) Armadillo/beta-catenin (CTNNB1; MIM 116806)-like (ARM) domains are imperfect 45-amino acid repeats involved in protein-protein interactions. ARM domain-containing proteins, such as ARMC3, function in signal transduction, development, cell adhesion and mobility, and tumor initiation and metastasis (Li et al., 2006 [PubMed 16915934]).[supplied by OMIM, Mar 2008]

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=0.2308453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMC3	NM_173081.5	c.454T>A	p.Leu152Ile	missense_variant	6/19	ENST00000298032.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMC3	ENST00000298032.10	c.454T>A	p.Leu152Ile	missense_variant	6/19	1	NM_173081.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.454T>A (p.L152I) alteration is located in exon 6 (coding exon 5) of the ARMC3 gene. This alteration results from a T to A substitution at nucleotide position 454, causing the leucine (L) at amino acid position 152 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0025	T;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.85	T;D;T;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.3	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.93	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.11	T;D;T;T
Sift4G	Benign	0.098	T;T;T;T
Polyphen		0.99	D;P;.;B
Vest4		0.54
MVP		0.56
MPC		0.50
ClinPred		0.92	D
GERP RS		-2.5
Varity_R		0.067
gMVP		0.17

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: rs1835101263; hg19: chr10-23248420;