rs202169392

Variant names:

• chr11-26553241-TTC-T
• rs202169392
• NM_031418.4:c.1290-5_1290-4delTC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_031418.4(ANO3):​c.1290-5_1290-4delTC variant causes a splice region, 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, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.576
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 412867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4091 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031418.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	NM_031418.4	MANE Select	c.1290-5_1290-4delTC		splice_region intron	N/A	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.1473-5_1473-4delTC		splice_region intron	N/A	NP_001300655.1	A0A5F9ZHL6
	ANO3	NM_001313727.2		c.852-5_852-4delTC		splice_region intron	N/A	NP_001300656.1	Q9BYT9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1290-7_1290-6delTC		splice_region intron	N/A	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.1473-7_1473-6delTC		splice_region intron	N/A	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.1242-7_1242-6delTC		splice_region intron	N/A	ENSP00000432576.1	E9PQ79

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

GnomAD2 exomes AF: 0.0302 AC: 7210 AN: 238746 AF XY: 0.0304

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 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

African (AFR) AF: 0.00511 AC: 163 AN: 31906

American (AMR) AF: 0.0126 AC: 542 AN: 43142

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 355 AN: 25330

East Asian (EAS) AF: 0.000557 AC: 22 AN: 39522

South Asian (SAS) AF: 0.0132 AC: 1096 AN: 82946

European-Finnish (FIN) AF: 0.0443 AC: 2217 AN: 49996

Middle Eastern (MID) AF: 0.00681 AC: 38 AN: 5580

European-Non Finnish (NFE) AF: 0.0436 AC: 46200 AN: 1060770

Other (OTH) AF: 0.0293 AC: 1706 AN: 58128

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

African (AFR) AF: 0.00732 AC: 303 AN: 41382

American (AMR) AF: 0.0172 AC: 262 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3468

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5140

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4802

European-Finnish (FIN) AF: 0.0337 AC: 352 AN: 10460

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0442 AC: 2993 AN: 67768

Other (OTH) AF: 0.0241 AC: 50 AN: 2076

Alfa AF: 0.0318 Hom.: 45

Bravo AF: 0.0249

Asia WGS AF: 0.00867 AC: 30 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ANO3-related disorder (1)
-	-	1	Dystonia 24 (1)
-	-	1	Dystonic disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.58
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs202169392; hg19: chr11-26574788;