rs4268466

Variant names:

• chr11-26641263-A-G
• rs4268466
• NM_031418.4:c.2142-633A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031418.4(ANO3):​c.2142-633A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 152,050 control chromosomes in the GnomAD database, including 11,729 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (11729 hom., cov: 32)
• Consequence: ANO3 NM_031418.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.279
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4	c.2142-633A>G		intron_variant	Intron 21 of 26	ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.2142-633A>G		intron_variant	Intron 21 of 26	1	NM_031418.4	ENSP00000256737.3
ANO3	ENST00000672621.1	c.2325-633A>G		intron_variant	Intron 22 of 27			ENSP00000500506.1
ANO3	ENST00000525139.5	c.2094-633A>G		intron_variant	Intron 21 of 26	5		ENSP00000432576.1
ANO3	ENST00000531568.1	c.1704-633A>G		intron_variant	Intron 18 of 23	2		ENSP00000432394.1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57438 AN: 151932 Hom.: 11720 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.378

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.378 AC: 57458 AN: 152050 Hom.: 11729 Cov.: 32 AF XY: 0.375 AC XY: 27875 AN XY: 74318

African (AFR) AF: 0.240 AC: 9956 AN: 41476

American (AMR) AF: 0.306 AC: 4675 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1528 AN: 3472

East Asian (EAS) AF: 0.354 AC: 1830 AN: 5166

South Asian (SAS) AF: 0.486 AC: 2339 AN: 4816

European-Finnish (FIN) AF: 0.380 AC: 4007 AN: 10554

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31862 AN: 67974

Other (OTH) AF: 0.380 AC: 802 AN: 2112

Alfa AF: 0.420 Hom.: 1821

Bravo AF: 0.364

Asia WGS AF: 0.410 AC: 1425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.0
DANN	Benign	0.63
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs4268466; hg19: chr11-26662810;