NM_031418.4:c.47G>T

Variant names:

• chr11-26441918-G-T
• rs1408780131
• NM_031418.4:c.47G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_031418.4(ANO3):​c.47G>T​(p.Gly16Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000011 in 1,457,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G16C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ANO3 NM_031418.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83
• 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, G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

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.47G>T	p.Gly16Val	missense splice_region	Exon 2 of 27	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.230G>T	p.Gly77Val	missense splice_region	Exon 3 of 28	NP_001300655.1	A0A5F9ZHL6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.47G>T	p.Gly16Val	missense splice_region	Exon 2 of 27	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000672621.1		c.230G>T	p.Gly77Val	missense splice_region	Exon 3 of 28	ENSP00000500506.1	A0A5F9ZHL6
	ANO3	ENST00000525139.5	TSL:5	c.-2G>T		splice_region	Exon 2 of 27	ENSP00000432576.1	E9PQ79

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1457166 Hom.: 0 Cov.: 30 AF XY: 0.00000966 AC XY: 7 AN XY: 724878

African (AFR) AF: 0.00 AC: 0 AN: 33164

American (AMR) AF: 0.00 AC: 0 AN: 43814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110156

Other (OTH) AF: 0.0000499 AC: 3 AN: 60162

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonic disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	0.081
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Uncertain	0.018	D
Sift4G	Benign	0.13	T
Polyphen		0.15	B
Vest4		0.68
MutPred		0.20		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.49
MPC		0.48
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.34
gMVP		0.37
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.010		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: rs1408780131; hg19: chr11-26463465;