3-138241822-T-G

Variant summary

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

The NM_001363941.2(ARMC8):c.877T>G(p.Leu293Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,754 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARMC8 NM_001363941.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

Genes affected

ARMC8 (HGNC:24999): (armadillo repeat containing 8) Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Located in cytosol and nucleoplasm. Part of ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.16695338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMC8	NM_001363941.2	c.877T>G	p.Leu293Val	missense_variant	11/22	ENST00000469044.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMC8	ENST00000469044.6	c.877T>G	p.Leu293Val	missense_variant	11/22	5	NM_001363941.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

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

Oct 04, 2022

The c.835T>G (p.L279V) alteration is located in exon 12 (coding exon 11) of the ARMC8 gene. This alteration results from a T to G substitution at nucleotide position 835, causing the leucine (L) at amino acid position 279 to be replaced by a valine (V). 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	0.13
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	17
Dann	Benign	0.97
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.20	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.23	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T
Polyphen		0.26, 0.96, 0.73, 0.17, 0.86	.;B;P;.;P;.;B;P;P;.
Vest4		0.52
MutPred		0.28		.;.;Loss of ubiquitination at K290 (P = 0.0877);.;.;.;.;.;Loss of ubiquitination at K290 (P = 0.0877);.;
MVP		0.43
MPC		0.74
ClinPred		0.35	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
gMVP		0.42

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: rs2046640666; hg19: chr3-137960664;