chr16-31464292-TAA-T

Variant names:

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

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_1371-78delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 484,612 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 27)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: ARMC5 NM_001105247.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.139
• 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 amr. GnomAd4 allele frequency = 0.00174 (207/118786) while in subpopulation AMR AF = 0.00128 (15/11676). AF 95% confidence interval is 0.000791. There are 1 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 207 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_1371-78delAA		intron	N/A	NP_001098717.1	Q96C12-1
	ARMC5	NM_001288767.2		c.1656-79_1656-78delAA		intron	N/A	NP_001275696.1	J3KQ26
	ARMC5	NM_001301820.1		c.1467-79_1467-78delAA		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_1371-100delAA		intron	N/A	ENSP00000268314.4	Q96C12-1
	ARMC5	ENST00000457010.6	TSL:1	c.1371-101_1371-100delAA		intron	N/A	ENSP00000399561.2	Q96C12-4
	ARMC5	ENST00000408912.7	TSL:2	c.1656-101_1656-100delAA		intron	N/A	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 208 AN: 118778 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000949

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00129

Gnomad ASJ AF: 0.0396

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000583

Gnomad OTH AF: 0.00190

GnomAD4 exome AF: 0.142 AC: 51868 AN: 365826 Hom.: 0 AF XY: 0.144 AC XY: 26697 AN XY: 184860

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

African (AFR) AF: 0.0966 AC: 832 AN: 8610

American (AMR) AF: 0.179 AC: 1382 AN: 7732

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 1432 AN: 8042

East Asian (EAS) AF: 0.174 AC: 3029 AN: 17360

South Asian (SAS) AF: 0.136 AC: 2195 AN: 16138

European-Finnish (FIN) AF: 0.137 AC: 3397 AN: 24866

Middle Eastern (MID) AF: 0.144 AC: 201 AN: 1394

European-Non Finnish (NFE) AF: 0.139 AC: 36587 AN: 263384

Other (OTH) AF: 0.154 AC: 2813 AN: 18300

⚠️ 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: 0.00174 AC: 207 AN: 118786 Hom.: 1 Cov.: 27 AF XY: 0.00178 AC XY: 101 AN XY: 56774

African (AFR) AF: 0.000916 AC: 29 AN: 31658

American (AMR) AF: 0.00128 AC: 15 AN: 11676

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 119 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: 0.00133 AC: 8 AN: 6022

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

European-Non Finnish (NFE) AF: 0.000583 AC: 33 AN: 56566

Other (OTH) AF: 0.00190 AC: 3 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		0.14
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;