3-43605720-CT-CTT

Variant names:

• chr3-43605720-C-CT
• rs540331226
• NM_018075.5:c.132dupA

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1 PM2 PP5_Very_Strong BS1_Supporting

The NM_018075.5(ANO10):​c.132dupA​(p.Asp45ArgfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,586,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: ANO10 NM_018075.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1
• Conservation: PhyloP100: 1.09

Genes affected

ANO10 (HGNC:25519): (anoctamin 10) The transmembrane protein encoded by this gene belongs to the anoctamin family of calcium-activated chloride channels, also known as the transmembrane 16 family. The encoded protein contains eight transmembrane domains with cytosolic N- and C-termini. Defects in this gene may cause autosomal recessive spinocerebellar ataxia-10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-43605720-C-CT is Pathogenic according to our data. Variant chr3-43605720-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000698 (1002/1435164) while in subpopulation NFE AF= 0.000821 (897/1092100). AF 95% confidence interval is 0.000776. There are 0 homozygotes in gnomad4_exome. There are 484 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO10	NM_018075.5	c.132dupA	p.Asp45ArgfsTer9	frameshift_variant	Exon 2 of 13	ENST00000292246.8	NP_060545.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO10	ENST00000292246.8	c.132dupA	p.Asp45ArgfsTer9	frameshift_variant	Exon 2 of 13	1	NM_018075.5	ENSP00000292246.3

Frequencies

GnomAD3 genomes AF: 0.000450 AC: 68 AN: 151084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.000288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000724

Gnomad OTH AF: 0.000482

GnomAD4 exome AF: 0.000698 AC: 1002 AN: 1435164 Hom.: 0 Cov.: 32 AF XY: 0.000677 AC XY: 484 AN XY: 714436

Gnomad4 AFR exome AF: 0.000366

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000157

Gnomad4 EAS exome AF: 0.000182

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.000231

Gnomad4 NFE exome AF: 0.000821

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000450 AC: 68 AN: 151200 Hom.: 0 Cov.: 32 AF XY: 0.000501 AC XY: 37 AN XY: 73898

Gnomad4 AFR AF: 0.000291

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.000288

Gnomad4 NFE AF: 0.000725

Gnomad4 OTH AF: 0.000477

Bravo AF: 0.000385

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 10 Pathogenic:8 Uncertain:1

Jun 24, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 24, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.132dup variant results in an amino acid frameshift and creates a premature stop codon 9 amino acids downstream of the change, p.Asp45Argfs*9. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ANO10 protein with potentially abnormal function. This sequence change has previously been described in the homozygous and compound heterozygous states in individuals with cerebellar ataxia (PMIDs: 25089919, 29482223, 25133958, 25664549, 31423897, 29915382). Functional studies have demonstrated that this sequence change decreases the expression of ANO10 (PMID: 25182700). It has been described in the gnomAD database with a population frequency of 0.058% in non-Finnish European subpopulation (dbSNP rs540331226). These collective evidences indicate that c.132dup (p.Asp45Argfs*9) is pathogenic. -

Nov 01, 2014

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000162016 / PMID: 25089919). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Jan 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ANO10 c.132dupA (p.Asp45ArgfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.132dupA has been reported in the literature in multiple individuals affected with Spinocerebellar ataxia 10 (Bogdanova-Mihaylova_2016). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 30838263). ClinVar contains an entry for this variant (Variation ID: 162016). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 19, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ANO10 c.132dup variant is classified as Pathogenic (PVS1, PS4, PM3) This ANO10 c.132dup variant is located in exon 2/13 and is predicted to cause a shift in the reading frame at codon 45. The variant has been reported in probands with a clinical presentation of OMIM:613728 (PS4). This variant is present at low frequency in population databases (PM2 not met). This variant has been detected in gnomAD 68 times, but consistently reported as pathogenic / likely pathogenic in the literature. This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). This variant has been reported in trans with other pathogenic variants PMID:25089919, 25182700 The variant has been reported in dbSNP (rs540331226) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 162016) -

Mar 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:8

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest that the variant results in a significant reduction of ANO10 expression (Balreira et al., 2014); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25664551, 27045840, 25133958, 25664549, 30515630, 31423897, 31980526, 25182700, 25089919, 29482223, 29915382) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ANO10: PM3:Very Strong, PVS1, PM2 -

Nov 14, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) In multiple individuals with clinical features associated with this gene, this variant has been seen with a single recessive pathogenic variant in the same gene. -

May 26, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2020

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asp45Argfs*9) in the ANO10 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANO10 are known to be pathogenic (PMID: 25089919). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with clinical features of cerebellar ataxia (PMID: 25089919, 25133958, 25182700). This variant is also known as c.123_124insA and c.132_133insT. ClinVar contains an entry for this variant (Variation ID: 162016). For these reasons, this variant has been classified as Pathogenic. -

Abnormal central motor function Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive cerebellar ataxia Pathogenic:1

May 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp45fs variant in ANO10 has been previously reported in 6 compound hetero zygous individuals and 2 homozygous individuals with adult-onset autosomal reces sive spinocerebellar ataxia (Renaud 2014, Balreira 2014, Fogel 2014, Minnerop 20 15). This variant has also been identified in 0.08% (12/14786) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs540331226). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency for autosomal recessive spinocerebellar ataxia. This variant has also be en reported by other clinical laboratories in ClinVar (Variation ID: 162016). Th is variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 45 and leads to a premature termination codo n 9 amino acids downstream. This alteration is then predicted to lead to a trunc ated or absent protein. In summary, the p.Asp45fs variant meets criteria to be c lassified as pathogenic for adult-onset autosomal recessive spinocerebellar atax ia. ACMG/AMP Criteria applied: PVS1; PM3_Strong. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs540331226; hg19: chr3-43647212;