11-26553243-C-T

Variant names:

• chr11-26553243-C-T
• rs770584529
• NM_031418.4:c.1290-6C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_031418.4(ANO3):​c.1290-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0084 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANO3 NM_031418.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003468
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.576
• Publications: 0 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, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 11-26553243-C-T is Benign according to our data. Variant chr11-26553243-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 455985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1290-6C>T		splice_region intron	N/A	NP_113606.2
	ANO3	NM_001313726.2		c.1473-6C>T		splice_region intron	N/A	NP_001300655.1
	ANO3	NM_001313727.2		c.852-6C>T		splice_region intron	N/A	NP_001300656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1290-6C>T		splice_region intron	N/A	ENSP00000256737.3
	ANO3	ENST00000672621.1		c.1473-6C>T		splice_region intron	N/A	ENSP00000500506.1
	ANO3	ENST00000525139.5	TSL:5	c.1242-6C>T		splice_region intron	N/A	ENSP00000432576.1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 429 AN: 103988 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00339

Gnomad AMI AF: 0.00192

Gnomad AMR AF: 0.00198

Gnomad ASJ AF: 0.00313

Gnomad EAS AF: 0.00215

Gnomad SAS AF: 0.00376

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00555

Gnomad OTH AF: 0.00444

GnomAD2 exomes AF: 0.0204 AC: 3078 AN: 150966 AF XY: 0.0213

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.00902

Gnomad ASJ exome AF: 0.0376

Gnomad EAS exome AF: 0.0100

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0201

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00838 AC: 7147 AN: 852534 Hom.: 4 Cov.: 24 AF XY: 0.00890 AC XY: 3809 AN XY: 427848

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00939 AC: 193 AN: 20560

American (AMR) AF: 0.00860 AC: 274 AN: 31878

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 246 AN: 16146

East Asian (EAS) AF: 0.00291 AC: 91 AN: 31264

South Asian (SAS) AF: 0.0198 AC: 1020 AN: 51456

European-Finnish (FIN) AF: 0.0115 AC: 359 AN: 31232

Middle Eastern (MID) AF: 0.0126 AC: 44 AN: 3492

European-Non Finnish (NFE) AF: 0.00743 AC: 4680 AN: 629972

Other (OTH) AF: 0.00657 AC: 240 AN: 36534

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00413 AC: 430 AN: 104030 Hom.: 0 Cov.: 26 AF XY: 0.00393 AC XY: 200 AN XY: 50910

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00338 AC: 101 AN: 29878

American (AMR) AF: 0.00198 AC: 22 AN: 11110

Ashkenazi Jewish (ASJ) AF: 0.00313 AC: 8 AN: 2560

East Asian (EAS) AF: 0.00215 AC: 9 AN: 4184

South Asian (SAS) AF: 0.00377 AC: 12 AN: 3184

European-Finnish (FIN) AF: 0.00348 AC: 22 AN: 6320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.00555 AC: 248 AN: 44712

Other (OTH) AF: 0.00512 AC: 7 AN: 1368

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00784 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.0
DANN	Benign	0.55
PhyloP100		0.58
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs770584529; hg19: chr11-26574790;