Genetic Variant ARMC5:c.1371-80_1371-78delAAA (chr16-31464292-TAAA-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is . The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001105247.2(ARMC5):c.1371-80_1371-78delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 492,250 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 0.000042 ( 0 hom., cov: 27)

Exomes 𝑓: 0.031 ( 0 hom. )

Consequence

ARMC5
NM_001105247.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.320

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), Genomics England PanelApp, Ambry Genetics
Cushing syndrome due to macronodular adrenal hyperplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARMC5 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001105247.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 5 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARMC5	NM_001105247.2	MANE Select	c.1371-80_1371-78delAAA	intron	N/A	NP_001098717.1	Q96C12-1
ARMC5	NM_001288767.2		c.1656-80_1656-78delAAA	intron	N/A	NP_001275696.1	J3KQ26
ARMC5	NM_001301820.1		c.1467-80_1467-78delAAA	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.1371-101_1371-99delAAA	intron	N/A	ENSP00000268314.4	Q96C12-1
ARMC5	ENST00000457010.6	TSL:1	c.1371-101_1371-99delAAA	intron	N/A	ENSP00000399561.2	Q96C12-4
ARMC5	ENST00000408912.7	TSL:2	c.1656-101_1656-99delAAA	intron	N/A	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes

AF:

0.0000421

AC:

AN:

118794

Hom.:

Cov.:

show subpopulations

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:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000707

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0312

AC:

11663

AN:

373448

Hom.:

AF XY:

0.0322

AC XY:

6073

AN XY:

188702

show subpopulations

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

African (AFR)

AF:

0.0208

AC:

185

AN:

8880

American (AMR)

AF:

0.0461

AC:

364

AN:

7900

Ashkenazi Jewish (ASJ)

AF:

0.0534

AC:

442

AN:

8282

East Asian (EAS)

AF:

0.0394

AC:

705

AN:

17916

South Asian (SAS)

AF:

0.0326

AC:

535

AN:

16404

European-Finnish (FIN)

AF:

0.0295

AC:

748

AN:

25350

Middle Eastern (MID)

AF:

0.0498

AC:

AN:

1426

European-Non Finnish (NFE)

AF:

0.0295

AC:

7936

AN:

268580

Other (OTH)

AF:

0.0362

AC:

677

AN:

18710

⚠️ 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: 0.282

Heterozygous variant carriers

1049

2098

3146

4195

5244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

122

244

366

488

610

<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

AF:

0.0000421

AC:

AN:

118802

Hom.:

Cov.:

AF XY:

0.0000704

AC XY:

AN XY:

56784

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31660

American (AMR)

AF:

0.00

AC:

AN:

11676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3008

East Asian (EAS)

AF:

0.00

AC:

AN:

4112

South Asian (SAS)

AF:

0.00

AC:

AN:

3168

European-Finnish (FIN)

AF:

0.000166

AC:

AN:

6034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.0000707

AC:

AN:

56568

Other (OTH)

AF:

0.00

AC:

AN:

1582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.32

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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16-31464292-TAAAAAAAAAAAAAAA-TAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over