rs1554976234

Variant names:

• chr11-26599697-A-T
• rs1554976234
• NM_031418.4:c.1819A>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_031418.4(ANO3):​c.1819A>T​(p.Ile607Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.29

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 11-26599697-A-T is Pathogenic according to our data. Variant chr11-26599697-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521283.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO3	NM_031418.4	c.1819A>T	p.Ile607Phe	missense_variant	Exon 17 of 27	ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO3	ENST00000256737.8	c.1819A>T	p.Ile607Phe	missense_variant	Exon 17 of 27	1	NM_031418.4	ENSP00000256737.3
ANO3	ENST00000672621.1	c.2002A>T	p.Ile668Phe	missense_variant	Exon 18 of 28			ENSP00000500506.1
ANO3	ENST00000525139.5	c.1771A>T	p.Ile591Phe	missense_variant	Exon 17 of 27	5		ENSP00000432576.1
ANO3	ENST00000531568.1	c.1381A>T	p.Ile461Phe	missense_variant	Exon 14 of 24	2		ENSP00000432394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dystonia 24 Pathogenic:1

Jun 12, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ANO3-related disorder as de novo (ClinVar ID: VCV000521283 /PMID: 30455893). A different missense change at the same codon (p.Ile607Thr) has been reported to be associated with ANO3-related disorder (PMID: 31228765). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases Uncertain:1

Oct 04, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	4.0	.;H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.93
MutPred		0.64		.;Loss of catalytic residue at L612 (P = 0.0447);.;
MVP		0.79
MPC		2.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.71
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1554976234; hg19: chr11-26621244;