rs3802751

Variant names:

• chr11-26537400-T-C
• rs3802751
• NM_031418.4:c.977-6T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031418.4(ANO3):​c.977-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,610,656 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (281 hom.)
• Consequence: ANO3 NM_031418.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006558
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.106
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-26537400-T-C is Benign according to our data. Variant chr11-26537400-T-C is described in ClinVar as Benign. ClinVar VariationId is 412869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.073 is higher than 0.05.

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.977-6T>C		splice_region intron	N/A	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.1160-6T>C		splice_region intron	N/A	NP_001300655.1	A0A5F9ZHL6
	ANO3	NM_001313727.2		c.539-6T>C		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.977-6T>C		splice_region intron	N/A	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.1160-6T>C		splice_region intron	N/A	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.929-6T>C		splice_region intron	N/A	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes AF: 0.00785 AC: 1194 AN: 152196 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0790

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0403

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.0116 AC: 2914 AN: 251374 AF XY: 0.0103

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.0699

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00549 AC: 8004 AN: 1458342 Hom.: 281 Cov.: 29 AF XY: 0.00536 AC XY: 3892 AN XY: 725758

African (AFR) AF: 0.000239 AC: 8 AN: 33414

American (AMR) AF: 0.0154 AC: 689 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00345 AC: 90 AN: 26114

East Asian (EAS) AF: 0.104 AC: 4112 AN: 39668

South Asian (SAS) AF: 0.00303 AC: 261 AN: 86188

European-Finnish (FIN) AF: 0.0331 AC: 1768 AN: 53404

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5762

European-Non Finnish (NFE) AF: 0.000689 AC: 764 AN: 1108812

Other (OTH) AF: 0.00498 AC: 300 AN: 60260

GnomAD4 genome AF: 0.00785 AC: 1196 AN: 152314 Hom.: 30 Cov.: 32 AF XY: 0.0106 AC XY: 793 AN XY: 74484

African (AFR) AF: 0.000337 AC: 14 AN: 41568

American (AMR) AF: 0.0148 AC: 226 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.0793 AC: 411 AN: 5180

South Asian (SAS) AF: 0.00372 AC: 18 AN: 4834

European-Finnish (FIN) AF: 0.0403 AC: 428 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68024

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00248 Hom.: 2

Bravo AF: 0.00593

Asia WGS AF: 0.0360 AC: 124 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000416

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs3802751; hg19: chr11-26558947; COSMIC: COSV56805368; COSMIC: COSV56805368;