11-26553243-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_031418.4(ANO3):​c.1290-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 880,048 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.0 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANO3 NM_031418.4 splice_region, intron
• Scores: Splicing: ADA: 0.01561
• Clinical Significance: Not reported in ClinVar
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4	c.1290-6C>G		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.1290-6C>G		splice_region_variant, intron_variant	Intron 12 of 26	1	NM_031418.4	ENSP00000256737.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 105120 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000364 AC: 32 AN: 880048 Hom.: 0 Cov.: 24 AF XY: 0.0000249 AC XY: 11 AN XY: 442256

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

African (AFR) AF: 0.000142 AC: 3 AN: 21114

American (AMR) AF: 0.00 AC: 0 AN: 32828

Ashkenazi Jewish (ASJ) AF: 0.0000591 AC: 1 AN: 16920

East Asian (EAS) AF: 0.00 AC: 0 AN: 31718

South Asian (SAS) AF: 0.00 AC: 0 AN: 54422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3632

European-Non Finnish (NFE) AF: 0.0000400 AC: 26 AN: 649546

Other (OTH) AF: 0.0000533 AC: 2 AN: 37516

⚠️ 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: AC0 AF: 0.00 AC: 0 AN: 105166 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 51426

African (AFR) AF: 0.00 AC: 0 AN: 30136

American (AMR) AF: 0.00 AC: 0 AN: 11214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2574

East Asian (EAS) AF: 0.00 AC: 0 AN: 4206

South Asian (SAS) AF: 0.00 AC: 0 AN: 3218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6404

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45310

Other (OTH) AF: 0.00 AC: 0 AN: 1380

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.6
DANN	Benign	0.61
PhyloP100		0.58
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.016
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.12		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;