rs199705068

chr11-26441908-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_031418.4(ANO3):c.47-10G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,602,040 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: ANO3 NM_031418.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001735
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.37

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-26441908-G-C is Benign according to our data. Variant chr11-26441908-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 526228.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-26441908-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000559 (85/152106) while in subpopulation AMR AF= 0.00105 (16/15276). AF 95% confidence interval is 0.000657. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO3	NM_031418.4	c.47-10G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000256737.8
ANO3	NM_001313726.2	c.230-10G>C		splice_polypyrimidine_tract_variant, intron_variant
ANO3	XM_047427399.1	c.47-10G>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO3	ENST00000256737.8	c.47-10G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_031418.4	P3
ANO3	ENST00000525139.5	c.-2-10G>C		splice_polypyrimidine_tract_variant, intron_variant		5
ANO3	ENST00000531646.1	c.47-10G>C		splice_polypyrimidine_tract_variant, intron_variant		4
ANO3	ENST00000672621.1	c.230-10G>C		splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 151986 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000457 AC: 111 AN: 243102 Hom.: 0 AF XY: 0.000419 AC XY: 55 AN XY: 131342

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.000671

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000470

Gnomad NFE exome AF: 0.000676

Gnomad OTH exome AF: 0.000508

GnomAD4 exome AF: 0.000703 AC: 1019 AN: 1449934 Hom.: 1 Cov.: 29 AF XY: 0.000674 AC XY: 486 AN XY: 721338

Gnomad4 AFR exome AF: 0.000244

Gnomad4 AMR exome AF: 0.000561

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000678

Gnomad4 NFE exome AF: 0.000821

Gnomad4 OTH exome AF: 0.000702

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74342

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000682 Hom.: 0

Bravo AF: 0.000461

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonic disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	17
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.19
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: rs199705068; hg19: chr11-26463455;