rs144792604

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_031418.4(ANO3):c.704A>G(p.Tyr235Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,610,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

ANO3
NM_031418.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.42

Publications

9 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 -9 ACMG points.

BP6

Variant 11-26525646-A-G is Benign according to our data. Variant chr11-26525646-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 388790.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00036 (525/1458882) while in subpopulation NFE AF = 0.000443 (492/1110676). AF 95% confidence interval is 0.000411. There are 0 homozygotes in GnomAdExome4. There are 271 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4 link	c.704A>G	p.Tyr235Cys	missense_variant	Exon 7 of 27	ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ANO3	ENST00000256737.8 link	c.704A>G	p.Tyr235Cys	missense_variant	Exon 7 of 27	1	NM_031418.4	ENSP00000256737.3
ANO3	ENST00000672621.1 link	c.887A>G	p.Tyr296Cys	missense_variant	Exon 8 of 28			ENSP00000500506.1
ANO3	ENST00000525139.5 link	c.656A>G	p.Tyr219Cys	missense_variant	Exon 7 of 27	5		ENSP00000432576.1
ANO3	ENST00000531568.1 link	c.266A>G	p.Tyr89Cys	missense_variant	Exon 4 of 24	2		ENSP00000432394.1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000265

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000262

AC:

AN:

248376

AF XY:

0.000290

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000890

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000497

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000360

AC:

525

AN:

1458882

Hom.:

Cov.:

AF XY:

0.000373

AC XY:

271

AN XY:

725680

show subpopulations

African (AFR)

AF:

0.0000900

AC:

AN:

33316

American (AMR)

AF:

0.0000677

AC:

AN:

44312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85626

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000443

AC:

492

AN:

1110676

Other (OTH)

AF:

0.000232

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000132

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000368

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000383

EpiControl

AF:

0.000358

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Nov 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 04, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24151159) -

Dystonia 24

Uncertain:1

May 01, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dystonic disorder

Uncertain:1

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 235 of the ANO3 protein (p.Tyr235Cys). This variant is present in population databases (rs144792604, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ANO3-related conditions. ClinVar contains an entry for this variant (Variation ID: 388790). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.080

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.6

.;M;.

PhyloP100

6.4

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.5

D;D;D

REVEL

Uncertain

0.52

Sift

Benign

0.056

T;D;T

Sift4G

Uncertain

0.056

T;D;T

Polyphen

1.0

.;D;.

Vest4

0.87

MVP

0.74

MPC

0.93

ClinPred

0.53

GERP RS

5.2

Varity_R

0.24

gMVP

0.60

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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