Genetic Variant NM_031418.4:c.1399T>G (chr11-26559731-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_031418.4(ANO3):c.1399T>G(p.Phe467Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F467I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ANO3
NM_031418.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.72

Publications

0 publications found

Variant links:

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 links:

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]

MUC15 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.843

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANO3	NM_031418.4	MANE Select	c.1399T>G	p.Phe467Val	missense	Exon 14 of 27	NP_113606.2	Q9BYT9-1
MUC15	NM_001135091.2	MANE Select	c.*1334A>C		3_prime_UTR	Exon 5 of 5	NP_001128563.1	A0A0A0MT67
ANO3	NM_001313726.2		c.1582T>G	p.Phe528Val	missense	Exon 15 of 28	NP_001300655.1	A0A5F9ZHL6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1399T>G	p.Phe467Val	missense	Exon 14 of 27	ENSP00000256737.3	Q9BYT9-1
MUC15	ENST00000529533.6	TSL:1 MANE Select	c.*1334A>C		3_prime_UTR	Exon 5 of 5	ENSP00000431983.1	A0A0A0MT67
ANO3	ENST00000672621.1		c.1582T>G	p.Phe528Val	missense	Exon 15 of 28	ENSP00000500506.1	A0A5F9ZHL6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

-0.020

MutationAssessor

Uncertain

2.7

PhyloP100

5.7

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.90

MutPred

0.54

Loss of catalytic residue at F467 (P = 0.0344)

MVP

0.71

MPC

2.1

ClinPred

1.0

GERP RS

5.5

Varity_R

0.91

gMVP

0.92

Mutation Taster

=28/72

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over