Genetic Variant ARMC5:c.1371-86_1371-78delAAAAAAAAA (chr16-31464292-TAAAAAAAAA-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is . The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001105247.2(ARMC5):c.1371-86_1371-78delAAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 499,396 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000076 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00092 ( 3 hom. )

Consequence

ARMC5
NM_001105247.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.28

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.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000758 (9/118806) while in subpopulation AFR AF = 0.000284 (9/31660). AF 95% confidence interval is 0.000148. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High AC in GnomAd4 at 9 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.1371-86_1371-78delAAAAAAAAA	intron	N/A	NP_001098717.1	Q96C12-1
ARMC5	NM_001288767.2		c.1656-86_1656-78delAAAAAAAAA	intron	N/A	NP_001275696.1	J3KQ26
ARMC5	NM_001301820.1		c.1467-86_1467-78delAAAAAAAAA	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_1371-93delAAAAAAAAA	intron	N/A	ENSP00000268314.4	Q96C12-1
ARMC5	ENST00000457010.6	TSL:1	c.1371-101_1371-93delAAAAAAAAA	intron	N/A	ENSP00000399561.2	Q96C12-4
ARMC5	ENST00000408912.7	TSL:2	c.1656-101_1656-93delAAAAAAAAA	intron	N/A	ENSP00000386125.3	J3KQ26

Frequencies

GnomAD3 genomes

AF:

0.0000673

AC:

AN:

118798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000253

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:

0.000922

AC:

351

AN:

380590

Hom.:

AF XY:

0.000811

AC XY:

156

AN XY:

192336

show subpopulations

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

African (AFR)

AF:

0.0316

AC:

284

AN:

8976

American (AMR)

AF:

0.00135

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:

0.000120

AC:

AN:

16648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25902

Middle Eastern (MID)

AF:

0.00137

AC:

AN:

1464

European-Non Finnish (NFE)

AF:

0.0000512

AC:

AN:

273404

Other (OTH)

AF:

0.00198

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: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0000758

AC:

AN:

118806

Hom.:

Cov.:

AF XY:

0.0000528

AC XY:

AN XY:

56788

show subpopulations

African (AFR)

AF:

0.000284

AC:

AN:

31660

American (AMR)

AF:

0.00

AC:

AN:

11678

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:

0.00

AC:

AN:

6034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

220

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56570

Other (OTH)

AF:

0.00

AC:

AN:

1582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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