3-138289107-G-C

Variant names:

• chr3-138289107-G-C
• NM_001363941.2:c.1881G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP3 BS2

The NM_001363941.2(ARMC8):​c.1881G>C​(p.Trp627Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ARMC8 NM_001363941.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363941.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC8	NM_001363941.2	MANE Select	c.1881G>C	p.Trp627Cys	missense	Exon 20 of 22	NP_001350870.1	Q8IUR7-1
	ARMC8	NM_015396.6		c.1839G>C	p.Trp613Cys	missense	Exon 21 of 23	NP_056211.2
	ARMC8	NM_001267041.2		c.1788G>C	p.Trp596Cys	missense	Exon 19 of 21	NP_001253970.1	B7Z637

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC8	ENST00000469044.6	TSL:5 MANE Select	c.1881G>C	p.Trp627Cys	missense	Exon 20 of 22	ENSP00000419413.1	Q8IUR7-1
	ARMC8	ENST00000481646.5	TSL:1	c.1839G>C	p.Trp613Cys	missense	Exon 21 of 23	ENSP00000420333.1	Q8IUR7-2
	NME9	ENST00000492993.5	TSL:1	n.*65+14400C>G		intron	N/A	ENSP00000419355.1	Q3KNW3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460454 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726492

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111102

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.53		Loss of catalytic residue at L625 (P = 0.0352)
MVP		0.62
MPC		1.9
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.76
gMVP		0.79
Mutation Taster		=24/76	disease causing

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

Other links and lift over

hg19: chr3-138007949;