6-35747417-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001286574.2(ARMC12):c.601G>T(p.Asp201Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,874 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARMC12 NM_001286574.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.79

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMC12	NM_001286574.2	c.601G>T	p.Asp201Tyr	missense_variant	4/6	ENST00000373866.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMC12	ENST00000373866.4	c.601G>T	p.Asp201Tyr	missense_variant	4/6	3	NM_001286574.2	A1
ARMC12	ENST00000288065.6	c.682G>T	p.Asp228Tyr	missense_variant	4/6	1		P3
ARMC12	ENST00000373869.7	c.601G>T	p.Asp201Tyr	missense_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251414 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	0.61	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.031	D;D;D
Sift4G	Uncertain	0.049	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.66
MutPred		0.69		.;Gain of helix (P = 0.1736);.;
MVP		0.43
MPC		0.46
ClinPred		0.96	D
GERP RS		3.6
Varity_R		0.25
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs193921111; hg19: chr6-35715194; COSMIC: COSV55359638;