Genetic Variant ARMC5:c.1371-82_1371-78dupAAAAA (chr16-31464292-T-TAAAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001105247.2(ARMC5):c.1371-82_1371-78dupAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000788 in 380,608 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 0.0 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ARMC5
NM_001105247.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.18

Publications

0 publications found

Variant links:

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

ARMC5 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARMC5	NM_001105247.2	MANE Select	c.1371-82_1371-78dupAAAAA	intron	N/A	NP_001098717.1	Q96C12-1
ARMC5	NM_001288767.2		c.1656-82_1656-78dupAAAAA	intron	N/A	NP_001275696.1	J3KQ26
ARMC5	NM_001301820.1		c.1467-82_1467-78dupAAAAA	intron	N/A	NP_001288749.1	Q96C12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARMC5	ENST00000268314.9	TSL:5 MANE Select	c.1371-102_1371-101insAAAAA	intron	N/A	ENSP00000268314.4	Q96C12-1
ARMC5	ENST00000457010.6	TSL:1	c.1371-102_1371-101insAAAAA	intron	N/A	ENSP00000399561.2	Q96C12-4
ARMC5	ENST00000408912.7	TSL:2	c.1656-102_1656-101insAAAAA	intron	N/A	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

118798

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000788

AC:

AN:

380608

Hom.:

AF XY:

0.00000520

AC XY:

AN XY:

192338

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

9000

American (AMR)

AF:

0.00

AC:

AN:

8120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8520

East Asian (EAS)

AF:

0.00

AC:

AN:

18406

South Asian (SAS)

AF:

0.00

AC:

AN:

16644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1464

European-Non Finnish (NFE)

AF:

0.0000110

AC:

AN:

273402

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

118798

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

56774

African (AFR)

AF:

0.00

AC:

AN:

31614

American (AMR)

AF:

0.00

AC:

AN:

11666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3008

East Asian (EAS)

AF:

0.00

AC:

AN:

4120

South Asian (SAS)

AF:

0.00

AC:

AN:

3182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56580

Other (OTH)

AF:

0.00

AC:

AN:

1578

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

Publications

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16-31464292-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over