rs202169392

Positions:

• chr11-26553241-TTC-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_031418.4(ANO3):​c.1290-5_1290-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,548,830 control chromosomes in the GnomAD database, including 2,171 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (106 hom., cov: 26)
  • Exomes 𝑓: 0.037 (2065 hom.)
• Consequence: ANO3 NM_031418.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.576

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 -16 ACMG points.

• BP6: Variant 11-26553241-TTC-T is Benign according to our data. Variant chr11-26553241-TTC-T is described in ClinVar as [Likely_benign]. Clinvar id is 412867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-26553241-TTC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.027 (4091/151510) while in subpopulation NFE AF= 0.0442 (2993/67768). AF 95% confidence interval is 0.0428. There are 106 homozygotes in gnomad4. There are 1850 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4091 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO3	NM_031418.4	c.1290-5_1290-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000256737.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO3	ENST00000256737.8	c.1290-5_1290-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_031418.4	P3

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4089 AN: 151394 Hom.: 106 Cov.: 26

Gnomad AFR AF: 0.00734

Gnomad AMI AF: 0.0243

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0121

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0442

Gnomad OTH AF: 0.0243

GnomAD3 exomes AF: 0.0302 AC: 7210 AN: 238746 Hom.: 275 AF XY: 0.0304 AC XY: 3921 AN XY: 129138

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0408

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0375 AC: 52339 AN: 1397320 Hom.: 2065 AF XY: 0.0365 AC XY: 25484 AN XY: 697920

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.000557

Gnomad4 SAS exome AF: 0.0132

Gnomad4 FIN exome AF: 0.0443

Gnomad4 NFE exome AF: 0.0436

Gnomad4 OTH exome AF: 0.0293

GnomAD4 genome AF: 0.0270 AC: 4091 AN: 151510 Hom.: 106 Cov.: 26 AF XY: 0.0250 AC XY: 1850 AN XY: 74022

Gnomad4 AFR AF: 0.00732

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.0337

Gnomad4 NFE AF: 0.0442

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0318 Hom.: 45

Bravo AF: 0.0249

Asia WGS AF: 0.00867 AC: 30 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ANO3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2019

This variant is classified as 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

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2021

- -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs202169392; hg19: chr11-26574788;