16-31464292-TAAAAAAAAAAAAAAA-TAAAAAAAAAAA

Variant names:

• chr16-31464292-TAAAA-T
• rs537788230
• NM_001105247.2:c.1371-81_1371-78delAAAA

Variant summary

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

The NM_001105247.2(ARMC5):​c.1371-81_1371-78delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 496,810 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000017 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0050 (0 hom.)
• Consequence: ARMC5 NM_001105247.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• 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 0 ACMG points.

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.1371-81_1371-78delAAAA		intron	N/A	NP_001098717.1	Q96C12-1
	ARMC5	NM_001288767.2		c.1656-81_1656-78delAAAA		intron	N/A	NP_001275696.1	J3KQ26
	ARMC5	NM_001301820.1		c.1467-81_1467-78delAAAA		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.1371-101_1371-98delAAAA		intron	N/A	ENSP00000268314.4	Q96C12-1
	ARMC5	ENST00000457010.6	TSL:1	c.1371-101_1371-98delAAAA		intron	N/A	ENSP00000399561.2	Q96C12-4
	ARMC5	ENST00000408912.7	TSL:2	c.1656-101_1656-98delAAAA		intron	N/A	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes AF: 0.0000253 AC: 3 AN: 118794 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00413

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000634

GnomAD4 exome AF: 0.00502 AC: 1899 AN: 378008 Hom.: 0 AF XY: 0.00522 AC XY: 997 AN XY: 191048

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

African (AFR) AF: 0.00469 AC: 42 AN: 8954

American (AMR) AF: 0.00721 AC: 58 AN: 8046

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 73 AN: 8446

East Asian (EAS) AF: 0.00602 AC: 110 AN: 18268

South Asian (SAS) AF: 0.00459 AC: 76 AN: 16558

European-Finnish (FIN) AF: 0.00463 AC: 119 AN: 25726

Middle Eastern (MID) AF: 0.00415 AC: 6 AN: 1446

European-Non Finnish (NFE) AF: 0.00483 AC: 1313 AN: 271562

Other (OTH) AF: 0.00537 AC: 102 AN: 19002

⚠️ 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: 0.0000168 AC: 2 AN: 118802 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 56786

African (AFR) AF: 0.0000316 AC: 1 AN: 31660

American (AMR) AF: 0.00 AC: 0 AN: 11678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3008

East Asian (EAS) AF: 0.00 AC: 0 AN: 4112

South Asian (SAS) AF: 0.00 AC: 0 AN: 3168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6032

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56568

Other (OTH) AF: 0.000632 AC: 1 AN: 1582

Alfa AF: 0.00 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32

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;