chr11-26559731-T-A

Variant names:

• chr11-26559731-T-A
• rs750189427
• NM_031418.4:c.1399T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031418.4(ANO3):​c.1399T>A​(p.Phe467Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F467F) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ANO3 NM_031418.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72
• 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]

MUC15 (HGNC:14956): (mucin 15, cell surface associated) Predicted to be located in Golgi lumen and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

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.1399T>A	p.Phe467Ile	missense	Exon 14 of 27	NP_113606.2	Q9BYT9-1
	MUC15	NM_001135091.2	MANE Select	c.*1334A>T		3_prime_UTR	Exon 5 of 5	NP_001128563.1	A0A0A0MT67
	ANO3	NM_001313726.2		c.1582T>A	p.Phe528Ile	missense	Exon 15 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.1399T>A	p.Phe467Ile	missense	Exon 14 of 27	ENSP00000256737.3	Q9BYT9-1
	MUC15	ENST00000529533.6	TSL:1 MANE Select	c.*1334A>T		3_prime_UTR	Exon 5 of 5	ENSP00000431983.1	A0A0A0MT67
	ANO3	ENST00000672621.1		c.1582T>A	p.Phe528Ile	missense	Exon 15 of 28	ENSP00000500506.1	A0A5F9ZHL6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251306 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.025	D
Polyphen		0.96	D
Vest4		0.91
MutPred		0.47		Loss of catalytic residue at F467 (P = 0.0169)
MVP		0.71
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.94
Mutation Taster		=49/51	disease causing

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: rs750189427; hg19: chr11-26581278;