rs150506041

Positions:

• chr11-26660315-A-G
• chr11-26660315-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_031418.4(ANO3):​c.2817A>G​(p.Pro939Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,613,518 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: ANO3 NM_031418.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.622

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-26660315-A-G is Benign according to our data. Variant chr11-26660315-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 412871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-26660315-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.622 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00135 (206/152298) while in subpopulation NFE AF= 0.00203 (138/68014). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO3	NM_031418.4	c.2817A>G	p.Pro939Pro	synonymous_variant	27/27	ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.2817A>G	p.Pro939Pro	synonymous_variant	27/27	1	NM_031418.4	ENSP00000256737.3
ANO3	ENST00000672621.1	c.3000A>G	p.Pro1000Pro	synonymous_variant	28/28			ENSP00000500506.1
ANO3	ENST00000525139.5	c.2769A>G	p.Pro923Pro	synonymous_variant	27/27	5		ENSP00000432576.1
ANO3	ENST00000531568.1	c.2379A>G	p.Pro793Pro	synonymous_variant	24/24	2		ENSP00000432394.1

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00155 AC: 388 AN: 250892 Hom.: 0 AF XY: 0.00147 AC XY: 199 AN XY: 135596

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000728

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000557

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00192 AC: 2805 AN: 1461220 Hom.: 8 Cov.: 31 AF XY: 0.00190 AC XY: 1381 AN XY: 726918

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000806

Gnomad4 ASJ exome AF: 0.00433

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00208

Gnomad4 NFE exome AF: 0.00212

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00116 AC XY: 86 AN XY: 74456

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.00129

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00303

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ANO3: BP4, BP7 -

ANO3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.6
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs150506041; hg19: chr11-26681862; COSMIC: COSV56783933;