Genetic Variant ANO3:c.1290-6C>T (chr11-26553243-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_031418.4(ANO3):c.1290-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 0 hom., cov: 26)

Exomes 𝑓: 0.0084 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

ANO3
NM_031418.4 splice_region, intron

Scores

Splicing: ADA: 0.00003468

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.576

Publications

0 publications found

Variant links:

Genes affected

ANO3 (HGNC:14004): (anoctamin 3) The protein encoded by this gene belongs to the TMEM16 family of predicted membrane proteins, that are also known as anoctamins. While little is known about the function of this gene, mutations in this gene have been associated with some cases of autosomal dominant craniocervical dystonia. Cells from individuals with a mutation in this gene exhibited abnormalities in endoplasmic reticulum-dependent calcium signaling. Studies in rat show that the rat ortholog of this protein interacts with, and modulates the activity of a sodium-activated potassium channel. Deletion of this gene caused increased pain sensitivity in the rat model system. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ANO3 Gene-Disease associations (from GenCC):

dystonia 24
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ANO3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 11-26553243-C-T is Benign according to our data. Variant chr11-26553243-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 455985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4 link	c.1290-6C>T		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000256737.8	NP_113606.2	Q9BYT9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8 link	c.1290-6C>T		splice_region_variant, intron_variant	Intron 12 of 26	1	NM_031418.4	ENSP00000256737.3		Q9BYT9-1

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

429

AN:

103988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00339

Gnomad AMI

AF:

0.00192

Gnomad AMR

AF:

0.00198

Gnomad ASJ

AF:

0.00313

Gnomad EAS

AF:

0.00215

Gnomad SAS

AF:

0.00376

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00555

Gnomad OTH

AF:

0.00444

GnomAD2 exomes

AF:

0.0204

AC:

3078

AN:

150966

AF XY:

0.0213

show subpopulations

Gnomad AFR exome

AF:

0.0226

Gnomad AMR exome

AF:

0.00902

Gnomad ASJ exome

AF:

0.0376

Gnomad EAS exome

AF:

0.0100

Gnomad FIN exome

AF:

0.0269

Gnomad NFE exome

AF:

0.0198

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00838

AC:

7147

AN:

852534

Hom.:

Cov.:

AF XY:

0.00890

AC XY:

3809

AN XY:

427848

show subpopulations

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

African (AFR)

AF:

0.00939

AC:

193

AN:

20560

American (AMR)

AF:

0.00860

AC:

274

AN:

31878

Ashkenazi Jewish (ASJ)

AF:

0.0152

AC:

246

AN:

16146

East Asian (EAS)

AF:

0.00291

AC:

AN:

31264

South Asian (SAS)

AF:

0.0198

AC:

1020

AN:

51456

European-Finnish (FIN)

AF:

0.0115

AC:

359

AN:

31232

Middle Eastern (MID)

AF:

0.0126

AC:

AN:

3492

European-Non Finnish (NFE)

AF:

0.00743

AC:

4680

AN:

629972

Other (OTH)

AF:

0.00657

AC:

240

AN:

36534

⚠️ 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: 0.285

Heterozygous variant carriers

718

1435

2153

2870

3588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<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: AS_VQSR

AF:

0.00413

AC:

430

AN:

104030

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

200

AN XY:

50910

show subpopulations

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

African (AFR)

AF:

0.00338

AC:

101

AN:

29878

American (AMR)

AF:

0.00198

AC:

AN:

11110

Ashkenazi Jewish (ASJ)

AF:

0.00313

AC:

AN:

2560

East Asian (EAS)

AF:

0.00215

AC:

AN:

4184

South Asian (SAS)

AF:

0.00377

AC:

AN:

3184

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

6320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.00555

AC:

248

AN:

44712

Other (OTH)

AF:

0.00512

AC:

AN:

1368

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.275

Heterozygous variant carriers

131

175

219

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:

0.00784

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 26, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dystonic disorder

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.0

(source)

DANN

Benign

0.55

PhyloP100

0.58

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000035

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over