16-31464292-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chr16-31464292-T-TAAAAAAA
• rs537788230
• NM_001105247.2:c.1371-84_1371-78dupAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001105247.2(ARMC5):​c.1371-84_1371-78dupAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 380,614 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000026 (0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1371-84_1371-78dupAAAAAAA		intron	N/A	NP_001098717.1	Q96C12-1
	ARMC5	NM_001288767.2		c.1656-84_1656-78dupAAAAAAA		intron	N/A	NP_001275696.1	J3KQ26
	ARMC5	NM_001301820.1		c.1467-84_1467-78dupAAAAAAA		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.1371-102_1371-101insAAAAAAA		intron	N/A	ENSP00000268314.4	Q96C12-1
	ARMC5	ENST00000457010.6	TSL:1	c.1371-102_1371-101insAAAAAAA		intron	N/A	ENSP00000399561.2	Q96C12-4
	ARMC5	ENST00000408912.7	TSL:2	c.1656-102_1656-101insAAAAAAA		intron	N/A	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000263 AC: 1 AN: 380614 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 192342

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

African (AFR) AF: 0.00 AC: 0 AN: 9000

American (AMR) AF: 0.00 AC: 0 AN: 8120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8520

East Asian (EAS) AF: 0.00 AC: 0 AN: 18406

South Asian (SAS) AF: 0.00 AC: 0 AN: 16648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1464

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 273404

Other (OTH) AF: 0.0000522 AC: 1 AN: 19150

⚠️ 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 Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs537788230; hg19: chr16-31475613;