Genetic Variant ARMC5:c.1371-78dupA (chr16-31464292-T-TA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is . The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001105247.2(ARMC5):c.1371-78dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 497,236 control chromosomes in the GnomAD database, including 464 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.052 ( 464 hom., cov: 27)

Exomes 𝑓: 0.029 ( 0 hom. )

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), 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: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

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

Frequencies

GnomAD3 genomes

AF:

0.0521

AC:

6178

AN:

118510

Hom.:

461

Cov.:

show subpopulations

Gnomad AFR

AF:

0.154

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.0203

Gnomad ASJ

AF:

0.000665

Gnomad EAS

AF:

0.0294

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.00149

Gnomad MID

AF:

0.00826

Gnomad NFE

AF:

0.00635

Gnomad OTH

AF:

0.0438

GnomAD4 exome

AF:

0.0286

AC:

10829

AN:

378720

Hom.:

AF XY:

0.0295

AC XY:

5655

AN XY:

191374

show subpopulations

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

African (AFR)

AF:

0.0445

AC:

395

AN:

8884

American (AMR)

AF:

0.0264

AC:

213

AN:

8060

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

171

AN:

8478

East Asian (EAS)

AF:

0.0335

AC:

611

AN:

18244

South Asian (SAS)

AF:

0.0793

AC:

1308

AN:

16502

European-Finnish (FIN)

AF:

0.0166

AC:

429

AN:

25782

Middle Eastern (MID)

AF:

0.0295

AC:

AN:

1456

European-Non Finnish (NFE)

AF:

0.0261

AC:

7101

AN:

272266

Other (OTH)

AF:

0.0293

AC:

558

AN:

19048

⚠️ 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: 0.326

Heterozygous variant carriers

866

1732

2599

3465

4331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

216

432

648

864

1080

<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:

0.0523

AC:

6193

AN:

118516

Hom.:

464

Cov.:

AF XY:

0.0528

AC XY:

2991

AN XY:

56634

show subpopulations

African (AFR)

AF:

0.154

AC:

4841

AN:

31384

American (AMR)

AF:

0.0203

AC:

237

AN:

11674

Ashkenazi Jewish (ASJ)

AF:

0.000665

AC:

AN:

3008

East Asian (EAS)

AF:

0.0294

AC:

121

AN:

4110

South Asian (SAS)

AF:

0.132

AC:

418

AN:

3168

European-Finnish (FIN)

AF:

0.00149

AC:

AN:

6034

Middle Eastern (MID)

AF:

0.00455

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.00635

AC:

359

AN:

56568

Other (OTH)

AF:

0.0468

AC:

AN:

1580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

215

429

644

858

1073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.00418

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(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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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