rs587776923

Variant names:

• chr11-26639153-A-G
• rs587776923
• NM_031418.4:c.2053A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_031418.4(ANO3):​c.2053A>G​(p.Ser685Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• Publications: 9 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

ENSG00000300991 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-26639153-A-G is Pathogenic according to our data. Variant chr11-26639153-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 39498.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	NM_031418.4	MANE Select	c.2053A>G	p.Ser685Gly	missense	Exon 21 of 27	NP_113606.2
	ANO3	NM_001313726.2		c.2236A>G	p.Ser746Gly	missense	Exon 22 of 28	NP_001300655.1
	ANO3	NM_001313727.2		c.1615A>G	p.Ser539Gly	missense	Exon 18 of 24	NP_001300656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.2053A>G	p.Ser685Gly	missense	Exon 21 of 27	ENSP00000256737.3
	ANO3	ENST00000672621.1		c.2236A>G	p.Ser746Gly	missense	Exon 22 of 28	ENSP00000500506.1
	ANO3	ENST00000525139.5	TSL:5	c.2005A>G	p.Ser669Gly	missense	Exon 21 of 27	ENSP00000432576.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Dystonia 24 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Benign	0.66
DEOGEN2	Benign	0.076	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.29	N
PhyloP100		9.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.39	N
REVEL	Uncertain	0.40
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		1.0	D
Vest4		0.65
MutPred		0.39		Loss of glycosylation at S685 (P = 0.0577)
MVP		0.65
MPC		1.7
ClinPred		0.74	D
GERP RS		5.8
Varity_R		0.28
gMVP		0.96
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs587776923; hg19: chr11-26660700;