16-31464292-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAA

Variant names:

• chr16-31464292-T-TAA
• rs537788230
• NM_001105247.2:c.1371-79_1371-78dupAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001105247.2(ARMC5):​c.1371-79_1371-78dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 498,660 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: 𝑓 0.00032 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0026 (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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00032 (38/118798) while in subpopulation AFR AF = 0.000853 (27/31652). AF 95% confidence interval is 0.000602. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 38 AD gene.

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.1371-79_1371-78dupAA		intron	N/A	NP_001098717.1	Q96C12-1
	ARMC5	NM_001288767.2		c.1656-79_1656-78dupAA		intron	N/A	NP_001275696.1	J3KQ26
	ARMC5	NM_001301820.1		c.1467-79_1467-78dupAA		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_1371-101insAA		intron	N/A	ENSP00000268314.4	Q96C12-1
	ARMC5	ENST00000457010.6	TSL:1	c.1371-102_1371-101insAA		intron	N/A	ENSP00000399561.2	Q96C12-4
	ARMC5	ENST00000408912.7	TSL:2	c.1656-102_1656-101insAA		intron	N/A	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes AF: 0.000320 AC: 38 AN: 118790 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000854

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000485

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000530

Gnomad OTH AF: 0.000634

GnomAD4 exome AF: 0.00257 AC: 975 AN: 379862 Hom.: 0 AF XY: 0.00268 AC XY: 515 AN XY: 191932

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

African (AFR) AF: 0.00368 AC: 33 AN: 8962

American (AMR) AF: 0.00321 AC: 26 AN: 8098

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 13 AN: 8516

East Asian (EAS) AF: 0.00256 AC: 47 AN: 18358

South Asian (SAS) AF: 0.00995 AC: 165 AN: 16576

European-Finnish (FIN) AF: 0.00100 AC: 26 AN: 25878

Middle Eastern (MID) AF: 0.00205 AC: 3 AN: 1464

European-Non Finnish (NFE) AF: 0.00226 AC: 617 AN: 272910

Other (OTH) AF: 0.00236 AC: 45 AN: 19100

⚠️ 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: 0.000320 AC: 38 AN: 118798 Hom.: 0 Cov.: 27 AF XY: 0.000264 AC XY: 15 AN XY: 56780

African (AFR) AF: 0.000853 AC: 27 AN: 31652

American (AMR) AF: 0.000171 AC: 2 AN: 11678

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

East Asian (EAS) AF: 0.000486 AC: 2 AN: 4112

South Asian (SAS) AF: 0.000631 AC: 2 AN: 3168

European-Finnish (FIN) AF: 0.000166 AC: 1 AN: 6034

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

European-Non Finnish (NFE) AF: 0.0000530 AC: 3 AN: 56570

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		-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;