NM_031418.4:c.10C>A

Variant names:

• chr11-26332285-C-A
• rs750220809
• NM_031418.4:c.10C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031418.4(ANO3):​c.10C>A​(p.His4Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H4H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35363424).

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.10C>A	p.His4Asn	missense	Exon 1 of 27	NP_113606.2	Q9BYT9-1
	ANO3	NM_001313726.2		c.229+22566C>A		intron	N/A	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.10C>A	p.His4Asn	missense	Exon 1 of 27	ENSP00000256737.3	Q9BYT9-1
	ANO3	ENST00000531646.1	TSL:4	c.10C>A	p.His4Asn	missense	Exon 1 of 5	ENSP00000435275.1	E9PKW2
	ANO3	ENST00000672621.1		c.229+22566C>A		intron	N/A	ENSP00000500506.1	A0A5F9ZHL6

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251486 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.16
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Polyphen		0.85	P
Vest4		0.53
MutPred		0.23		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.72
MPC		0.25
ClinPred		0.63	D
GERP RS		5.9
PromoterAI		-0.040	Neutral
Varity_R		0.26
gMVP		0.45
Mutation Taster		=73/27	polymorphism

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: rs750220809; hg19: chr11-26353832;