rs770584529

Positions:

• chr11-26553243-C-A
• chr11-26553243-C-G
• chr11-26553243-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_031418.4(ANO3):​c.1290-6C>A 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 0.000662 in 877,756 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00066 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANO3 NM_031418.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001479
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.576

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000662 (581/877756) while in subpopulation AFR AF= 0.00128 (27/21022). AF 95% confidence interval is 0.000907. There are 1 homozygotes in gnomad4_exome. There are 273 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 581 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO3	NM_031418.4	c.1290-6C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.1290-6C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_031418.4	ENSP00000256737	P3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7 AN: 105112 Hom.: 0 Cov.: 26 FAILED QC

Gnomad AFR AF: 0.0000333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000310

Gnomad FIN AF: 0.000156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000662 AC: 581 AN: 877756 Hom.: 1 Cov.: 24 AF XY: 0.000619 AC XY: 273 AN XY: 441202

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000710

Gnomad4 EAS exome AF: 0.0000947

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.000768

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000666 AC: 7 AN: 105158 Hom.: 0 Cov.: 26 AF XY: 0.0000583 AC XY: 3 AN XY: 51424

Gnomad4 AFR AF: 0.0000332

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000311

Gnomad4 FIN AF: 0.000156

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.7
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.070		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: rs770584529; hg19: chr11-26574790;