3-138270061-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001363941.2(ARMC8):c.1408G>A(p.Val470Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,613,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: ARMC8 NM_001363941.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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]

NME9 (HGNC:21343): (NME/NM23 family member 9) Predicted to enable nucleoside diphosphate kinase activity. Predicted to be involved in nucleotide metabolic process. Predicted to be located in dynein axonemal particle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03697592).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMC8	NM_001363941.2	c.1408G>A	p.Val470Ile	missense_variant	16/22	ENST00000469044.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMC8	ENST00000469044.6	c.1408G>A	p.Val470Ile	missense_variant	16/22	5	NM_001363941.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151896 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000964 AC: 24 AN: 248960 Hom.: 0 AF XY: 0.0000740 AC XY: 10 AN XY: 135054

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461074 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19 AN XY: 726832

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74312

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000828 AC: 10

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

Aug 08, 2022

The c.1366G>A (p.V456I) alteration is located in exon 17 (coding exon 16) of the ARMC8 gene. This alteration results from a G to A substitution at nucleotide position 1366, causing the valine (V) at amino acid position 456 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	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.88	D;T;T;T;D;D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.037	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.10	N;N;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.42	T;T;T;T;T;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.0040, 0.0, 0.0010	.;B;B;.;.;B
Vest4		0.14
MutPred		0.53		.;.;Gain of catalytic residue at V470 (P = 0.0823);.;.;.;
MVP		0.22
MPC		0.51
ClinPred		0.084	T
GERP RS		4.6
Varity_R		0.038
gMVP		0.063

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: rs762109184; hg19: chr3-137988903; COSMIC: COSV104400171; COSMIC: COSV104400171;