NM_031418.4:c.1290-6C>A

Variant names:

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

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>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 877,756 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000067 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00066 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANO3 NM_031418.4 splice_region, intron
• Scores: Splicing: ADA: 0.001479
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031418.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	NM_031418.4	MANE Select	c.1290-6C>A		splice_region intron	N/A	NP_113606.2
	ANO3	NM_001313726.2		c.1473-6C>A		splice_region intron	N/A	NP_001300655.1
	ANO3	NM_001313727.2		c.852-6C>A		splice_region intron	N/A	NP_001300656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1290-6C>A		splice_region intron	N/A	ENSP00000256737.3
	ANO3	ENST00000672621.1		c.1473-6C>A		splice_region intron	N/A	ENSP00000500506.1
	ANO3	ENST00000525139.5	TSL:5	c.1242-6C>A		splice_region intron	N/A	ENSP00000432576.1

Frequencies

GnomAD3 genomes AF: 0.0000666 AC: 7 AN: 105112 Hom.: 0 Cov.: 26

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

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

African (AFR) AF: 0.00128 AC: 27 AN: 21022

American (AMR) AF: 0.00 AC: 0 AN: 32818

Ashkenazi Jewish (ASJ) AF: 0.000710 AC: 12 AN: 16898

East Asian (EAS) AF: 0.0000947 AC: 3 AN: 31692

South Asian (SAS) AF: 0.000202 AC: 11 AN: 54392

European-Finnish (FIN) AF: 0.000124 AC: 4 AN: 32330

Middle Eastern (MID) AF: 0.000276 AC: 1 AN: 3626

European-Non Finnish (NFE) AF: 0.000768 AC: 497 AN: 647544

Other (OTH) AF: 0.000695 AC: 26 AN: 37434

⚠️ 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: AS_VQSR AF: 0.0000666 AC: 7 AN: 105158 Hom.: 0 Cov.: 26 AF XY: 0.0000583 AC XY: 3 AN XY: 51424

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

African (AFR) AF: 0.0000332 AC: 1 AN: 30132

American (AMR) AF: 0.00 AC: 0 AN: 11212

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

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

South Asian (SAS) AF: 0.000311 AC: 1 AN: 3220

European-Finnish (FIN) AF: 0.000156 AC: 1 AN: 6402

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 4 AN: 45310

Other (OTH) AF: 0.00 AC: 0 AN: 1378

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000756906), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.7
DANN	Benign	0.60
PhyloP100		0.58
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs770584529; hg19: chr11-26574790;