rs3802751

Positions:

• chr11-26537400-T-C

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006558
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.106

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO3	NM_031418.4	c.977-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000256737.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO3	ENST00000256737.8	c.977-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_031418.4	P3
ANO3	ENST00000525139.5	c.929-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
ANO3	ENST00000531568.1	c.539-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		A1
ANO3	ENST00000672621.1	c.1160-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

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

GnomAD3 exomes AF: 0.0116 AC: 2914 AN: 251374 Hom.: 62 AF XY: 0.0103 AC XY: 1405 AN XY: 135860

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 SAS exome AF: 0.00284

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

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.00345

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.00303

Gnomad4 FIN exome AF: 0.0331

Gnomad4 NFE exome AF: 0.000689

Gnomad4 OTH exome AF: 0.00498

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

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0793

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.0403

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00268 Hom.: 2

Bravo AF: 0.00593

Asia WGS AF: 0.0360 AC: 124 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000416

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

- -

Dystonia 24 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Dystonic disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

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