11-26441992-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031418.4(ANO3):c.121G>C(p.Ala41Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. A41T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25713772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANO3	NM_031418.4	c.121G>C	p.Ala41Pro	missense_variant	2/27	ENST00000256737.8
ANO3	NM_001313726.2	c.304G>C	p.Ala102Pro	missense_variant	3/28
ANO3	XM_047427399.1	c.121G>C	p.Ala41Pro	missense_variant	2/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANO3	ENST00000256737.8	c.121G>C	p.Ala41Pro	missense_variant	2/27	1	NM_031418.4	P3
ANO3	ENST00000672621.1	c.304G>C	p.Ala102Pro	missense_variant	3/28
ANO3	ENST00000525139.5	c.73G>C	p.Ala25Pro	missense_variant	2/27	5
ANO3	ENST00000531646.1	c.121G>C	p.Ala41Pro	missense_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251428 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonic disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 20, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANO3 protein function. This variant has not been reported in the literature in individuals affected with ANO3-related conditions. This variant is present in population databases (rs150999282, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 41 of the ANO3 protein (p.Ala41Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.075	T;T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.036	D;D;T
Polyphen		0.90	.;P;.
Vest4		0.49
MutPred		0.16		.;Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);
MVP		0.61
MPC		0.57
ClinPred		0.54	D
GERP RS		4.3
Varity_R		0.39
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs150999282; hg19: chr11-26463539;