6-35747589-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_001286574.2(ARMC12):c.632G>A(p.Arg211Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,848 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ARMC12 NM_001286574.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.58

Genes affected

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a repeat ARM 2 (size 39) in uniprot entity ARM12_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001286574.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813
• PP5: Variant 6-35747589-G-A is Pathogenic according to our data. Variant chr6-35747589-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3024456.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-35747589-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMC12	NM_001286574.2	c.632G>A	p.Arg211Gln	missense_variant	5/6	ENST00000373866.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMC12	ENST00000373866.4	c.632G>A	p.Arg211Gln	missense_variant	5/6	3	NM_001286574.2	A1
ARMC12	ENST00000288065.6	c.713G>A	p.Arg238Gln	missense_variant	5/6	1		P3
ARMC12	ENST00000373869.7	c.632G>A	p.Arg211Gln	missense_variant	5/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 90 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.0088	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.028
Eigen_PC	Benign	-0.035
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.021	D;D;D
Sift4G	Benign	0.086	T;T;T
Polyphen		0.98	D;D;.
Vest4		0.62
MutPred		0.74		.;Gain of catalytic residue at R238 (P = 0.2948);.;
MVP		0.49
MPC		0.47
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.094
gMVP		0.38

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: rs200319789; hg19: chr6-35715366; COSMIC: COSV55361565;