16-31464292-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAA

Variant names:

• chr16-31464292-TA-T
• rs537788230
• NM_001105247.2:c.1371-78delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001105247.2(ARMC5):​c.1371-78delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 496,534 control chromosomes in the GnomAD database, including 73 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.023 (65 hom., cov: 27)
  • Exomes 𝑓: 0.23 (8 hom.)
• Consequence: ARMC5 NM_001105247.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• Publications: 0 publications found

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]

ARMC5 Gene-Disease associations (from GenCC):

• ACTH-independent macronodular adrenal hyperplasia 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Cushing syndrome due to macronodular adrenal hyperplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105247.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC5	NM_001105247.2	MANE Select	c.1371-78delA		intron	N/A	NP_001098717.1	Q96C12-1
	ARMC5	NM_001288767.2		c.1656-78delA		intron	N/A	NP_001275696.1	J3KQ26
	ARMC5	NM_001301820.1		c.1467-78delA		intron	N/A	NP_001288749.1	Q96C12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMC5	ENST00000268314.9	TSL:5 MANE Select	c.1371-101delA		intron	N/A	ENSP00000268314.4	Q96C12-1
	ARMC5	ENST00000457010.6	TSL:1	c.1371-101delA		intron	N/A	ENSP00000399561.2	Q96C12-4
	ARMC5	ENST00000408912.7	TSL:2	c.1656-101delA		intron	N/A	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 2781 AN: 118728 Hom.: 66 Cov.: 27

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.000332

Gnomad EAS AF: 0.00340

Gnomad SAS AF: 0.00346

Gnomad FIN AF: 0.00911

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00755

Gnomad OTH AF: 0.0133

GnomAD4 exome AF: 0.232 AC: 87781 AN: 377800 Hom.: 8 AF XY: 0.234 AC XY: 44657 AN XY: 190938

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.174 AC: 1497 AN: 8590

American (AMR) AF: 0.239 AC: 1916 AN: 8016

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 1995 AN: 8438

East Asian (EAS) AF: 0.250 AC: 4552 AN: 18214

South Asian (SAS) AF: 0.229 AC: 3790 AN: 16556

European-Finnish (FIN) AF: 0.198 AC: 5101 AN: 25754

Middle Eastern (MID) AF: 0.232 AC: 338 AN: 1458

European-Non Finnish (NFE) AF: 0.236 AC: 64108 AN: 271822

Other (OTH) AF: 0.237 AC: 4484 AN: 18952

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0234 AC: 2780 AN: 118734 Hom.: 65 Cov.: 27 AF XY: 0.0227 AC XY: 1289 AN XY: 56756

African (AFR) AF: 0.0652 AC: 2060 AN: 31586

American (AMR) AF: 0.0164 AC: 191 AN: 11674

Ashkenazi Jewish (ASJ) AF: 0.000332 AC: 1 AN: 3008

East Asian (EAS) AF: 0.00340 AC: 14 AN: 4112

South Asian (SAS) AF: 0.00347 AC: 11 AN: 3168

European-Finnish (FIN) AF: 0.00911 AC: 55 AN: 6038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.00755 AC: 427 AN: 56572

Other (OTH) AF: 0.0133 AC: 21 AN: 1582

Alfa AF: 0.000922 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs537788230; hg19: chr16-31475613;