Genetic Variant ARMC12:p.Arg211Leu (chr6-35747589-G-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The NM_001286574.2(ARMC12):c.632G>T(p.Arg211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R211Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ARMC12
NM_001286574.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.58

Publications

0 publications found

Variant links:

Genes affected

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

ARMC12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-35747589-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3024456.Status of the report is no_assertion_criteria_provided, 0 stars.

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).

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286574.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARMC12	NM_001286574.2	MANE Select	c.632G>T	p.Arg211Leu	missense	Exon 5 of 6	NP_001273503.1	Q5T9G4-1
ARMC12	NM_145028.5		c.713G>T	p.Arg238Leu	missense	Exon 5 of 6	NP_659465.2
ARMC12	NM_001286576.2		c.632G>T	p.Arg211Leu	missense	Exon 5 of 6	NP_001273505.1	Q5T9G4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARMC12	ENST00000373866.4	TSL:3 MANE Select	c.632G>T	p.Arg211Leu	missense	Exon 5 of 6	ENSP00000362973.3	Q5T9G4-1
ARMC12	ENST00000288065.6	TSL:1	c.713G>T	p.Arg238Leu	missense	Exon 5 of 6	ENSP00000288065.2	Q5T9G4-2
ARMC12	ENST00000373869.7	TSL:2	c.632G>T	p.Arg211Leu	missense	Exon 5 of 6	ENSP00000362976.3	Q5T9G4-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.56

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

0.066

Eigen_PC

Benign

-0.0093

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.82

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

2.6

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.23

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.037

Polyphen

0.98

Vest4

0.71

MutPred

0.71

Loss of solvent accessibility (P = 0.1077)

MVP

0.43

MPC

0.51

ClinPred

0.94

GERP RS

4.7

Varity_R

0.31

gMVP

0.58

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over