rs1378436915

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031418.4(ANO3):c.257A>G(p.Asn86Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Consequence

ANO3
NM_031418.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.135

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046764076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4 link	c.257A>G	p.Asn86Ser	missense_variant	Exon 3 of 27	ENST00000256737.8	NP_113606.2	Q9BYT9-1
ANO3	NM_001313726.2 link	c.440A>G	p.Asn147Ser	missense_variant	Exon 4 of 28		NP_001300655.1	Q9BYT9A0A5F9ZHL6B7Z9B9
ANO3	XM_047427399.1 link	c.257A>G	p.Asn86Ser	missense_variant	Exon 3 of 26		XP_047283355.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANO3	ENST00000256737.8 link	c.257A>G	p.Asn86Ser	missense_variant	Exon 3 of 27	1	NM_031418.4	ENSP00000256737.3	Q9BYT9-1
ANO3	ENST00000672621.1 link	c.440A>G	p.Asn147Ser	missense_variant	Exon 4 of 28			ENSP00000500506.1	A0A5F9ZHL6
ANO3	ENST00000525139.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 3 of 27	5		ENSP00000432576.1	E9PQ79
ANO3	ENST00000531646.1 link	c.257A>G	p.Asn86Ser	missense_variant	Exon 3 of 5	4		ENSP00000435275.1	E9PKW2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dystonic disorder

Uncertain:1

Feb 22, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine with serine at codon 86 of the ANO3 protein (p.Asn86Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ANO3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.90

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.072

T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.025

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

.;N;.

PhyloP100

0.14

PrimateAI

Benign

0.34

PROVEAN

Benign

0.15

N;N;N

REVEL

Benign

0.054

Sift

Benign

0.90

T;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.090

MutPred

0.14

.;Gain of phosphorylation at N86 (P = 0.0613);Gain of phosphorylation at N86 (P = 0.0613);

MVP

0.21

MPC

0.17

ClinPred

0.044

GERP RS

-0.77

Varity_R

0.028

gMVP

0.097

Mutation Taster

=99/1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over