16-31459325-A-C

Position:

• chr16-31459325-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024742.2(ARMC5):​c.-200A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,535,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: ARMC5 NM_024742.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.533

Genes affected

ARMC5 (HGNC:25781): (armadillo repeat containing 5) This gene encodes a member of the ARM (armadillo/beta-catenin-like repeat) superfamily. The ARM repeat is a tandemly repeated sequence motif with approximately 40 amino acid long. This repeat is implicated in mediating protein-protein interactions. The encoded protein contains seven ARM repeats. Mutations in this gene are associated with primary bilateral macronodular adrenal hyperplasia, which is also known as ACTH-independent macronodular adrenal hyperplasia 2. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

ENSG00000260267 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-31459325-A-C is Benign according to our data. Variant chr16-31459325-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3038470.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000723 (110/152234) while in subpopulation NFE AF= 0.00121 (82/67990). AF 95% confidence interval is 0.000996. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARMC5	NM_024742.2	c.-200A>C		5_prime_UTR_premature_start_codon_gain_variant	1/4		NP_079018.1
ARMC5	XM_047434651.1	c.-200A>C		5_prime_UTR_premature_start_codon_gain_variant	1/6		XP_047290607.1
ARMC5	NM_001301820.1	c.24A>C	p.Gly8Gly	synonymous_variant	1/7		NP_001288749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARMC5	ENST00000457010	c.-200A>C		5_prime_UTR_premature_start_codon_gain_variant	1/4	1		ENSP00000399561.2
ARMC5	ENST00000457010	c.-200A>C		5_prime_UTR_variant	1/4	1		ENSP00000399561.2
ARMC5	ENST00000563544	c.-73A>C		5_prime_UTR_premature_start_codon_gain_variant	1/7	2		ENSP00000456877.1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000689 AC: 93 AN: 134944 Hom.: 0 AF XY: 0.000654 AC XY: 48 AN XY: 73366

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000736

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000534

Gnomad FIN exome AF: 0.000184

Gnomad NFE exome AF: 0.000978

Gnomad OTH exome AF: 0.00193

GnomAD4 exome AF: 0.000816 AC: 1128 AN: 1382790 Hom.: 0 Cov.: 35 AF XY: 0.000856 AC XY: 584 AN XY: 682392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000644

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000395

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.000965

Gnomad4 OTH exome AF: 0.000484

GnomAD4 genome AF: 0.000723 AC: 110 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74444

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000933 Hom.: 1

Bravo AF: 0.000786

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ARMC5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.5
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs147875284; hg19: chr16-31470646;