rs142208066

Variant names:

• chr6-35738400-C-T
• rs142208066
• NM_001286574.2:c.326C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001286574.2(ARMC12):​c.326C>T​(p.Thr109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: ARMC12 NM_001286574.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.603
• Publications: 1 publications found

Genes affected

ARMC12 (HGNC:21099): (armadillo repeat containing 12) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.27213 (below the threshold of 3.09). Trascript score misZ: 1.0694 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.031053483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMC12	NM_001286574.2	c.326C>T	p.Thr109Met	missense_variant	Exon 3 of 6	ENST00000373866.4	NP_001273503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMC12	ENST00000373866.4	c.326C>T	p.Thr109Met	missense_variant	Exon 3 of 6	3	NM_001286574.2	ENSP00000362973.3

Frequencies

GnomAD3 genomes AF: 0.000211 AC: 32 AN: 151710 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000796 AC: 20 AN: 251286 AF XY: 0.0000368

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461792 Hom.: 0 Cov.: 33 AF XY: 0.0000523 AC XY: 38 AN XY: 727202

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111952

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.000211 AC: 32 AN: 151710 Hom.: 0 Cov.: 30 AF XY: 0.000203 AC XY: 15 AN XY: 74048

African (AFR) AF: 0.000678 AC: 28 AN: 41280

American (AMR) AF: 0.000131 AC: 2 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67982

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.407C>T (p.T136M) alteration is located in exon 3 (coding exon 3) of the ARMC12 gene. This alteration results from a C to T substitution at nucleotide position 407, causing the threonine (T) at amino acid position 136 to be replaced by a methionine (M). 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	0.079
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.83
DEOGEN2	Benign	0.0089	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0088	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N
PhyloP100		-0.60
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.84	N;N;N
REVEL	Benign	0.025
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.26
MVP		0.10
MPC		0.12
ClinPred		0.0077	T
GERP RS		-5.4
Varity_R		0.014
gMVP		0.081
Mutation Taster		=96/4	polymorphism

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

dbSNP: rs142208066; hg19: chr6-35706177;