11-26442035-C-T

Position:

chr11-26442035-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_031418.4(ANO3):c.164C>T(p.Ser55Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00731 in 1,614,172 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0076 ( 60 hom. )

Consequence

ANO3
NM_031418.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 4.58

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008046448).

BP6

Variant 11-26442035-C-T is Benign according to our data. Variant chr11-26442035-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412872.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}. Variant chr11-26442035-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0045 (686/152330) while in subpopulation NFE AF= 0.00745 (507/68032). AF 95% confidence interval is 0.00692. There are 2 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 686 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO3	NM_031418.4 linkuse as main transcript	c.164C>T	p.Ser55Phe	missense_variant	2/27	ENST00000256737.8	NP_113606.2	Q9BYT9-1
ANO3	NM_001313726.2 linkuse as main transcript	c.347C>T	p.Ser116Phe	missense_variant	3/28		NP_001300655.1	Q9BYT9A0A5F9ZHL6B7Z9B9
ANO3	XM_047427399.1 linkuse as main transcript	c.164C>T	p.Ser55Phe	missense_variant	2/26		XP_047283355.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ANO3	ENST00000256737.8 linkuse as main transcript	c.164C>T	p.Ser55Phe	missense_variant	2/27	1	NM_031418.4	ENSP00000256737.3	Q9BYT9-1
ANO3	ENST00000672621.1 linkuse as main transcript	c.347C>T	p.Ser116Phe	missense_variant	3/28			ENSP00000500506.1	A0A5F9ZHL6
ANO3	ENST00000525139.5 linkuse as main transcript	c.116C>T	p.Ser39Phe	missense_variant	2/27	5		ENSP00000432576.1	E9PQ79
ANO3	ENST00000531646.1 linkuse as main transcript	c.164C>T	p.Ser55Phe	missense_variant	2/5	4		ENSP00000435275.1	E9PKW2

Frequencies

GnomAD3 genomes

AF:

0.00451

AC:

686

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00208

Gnomad FIN

AF:

0.00640

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00745

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00519

AC:

1306

AN:

251454

Hom.:

AF XY:

0.00532

AC XY:

723

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00359

Gnomad FIN exome

AF:

0.00721

Gnomad NFE exome

AF:

0.00800

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00760

AC:

11110

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00746

AC XY:

5426

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00359

Gnomad4 FIN exome

AF:

0.00715

Gnomad4 NFE exome

AF:

0.00892

Gnomad4 OTH exome

AF:

0.00560

GnomAD4 genome

AF:

0.00450

AC:

686

AN:

152330

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

327

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00139

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.00640

Gnomad4 NFE

AF:

0.00745

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00704

Hom.:

Bravo

AF:

0.00418

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.00501

AC:

608

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00788

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ANO3: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

The c.164C>T (p.S55F) alteration is located in exon 2 (coding exon 2) of the ANO3 gene. This alteration results from a C to T substitution at nucleotide position 164, causing the serine (S) at amino acid position 55 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Dystonia 24

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Dystonic disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

T;T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

T;T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.0080

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.6

.;L;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.65

MVP

0.67

MPC

0.77

ClinPred

0.011

GERP RS

5.2

Varity_R

0.24

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over