rs15783

Variant names:

• chr11-26565254-G-A
• rs15783
• NM_001135091.2:c.686C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001135091.2(MUC15):​c.686C>T​(p.Thr229Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 1,583,798 control chromosomes in the GnomAD database, including 332,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T229T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.62 (29615 hom., cov: 31)
  • Exomes 𝑓: 0.65 (302962 hom.)
• Consequence: MUC15 NM_001135091.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 32 publications found

Genes affected

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]

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3498485E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135091.2. 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
	MUC15	NM_001135091.2	MANE Select	c.686C>T	p.Thr229Ile	missense	Exon 3 of 5	NP_001128563.1	A0A0A0MT67
	ANO3	NM_031418.4	MANE Select	c.1447+5475G>A		intron	N/A	NP_113606.2	Q9BYT9-1
	MUC15	NM_145650.4		c.605C>T	p.Thr202Ile	missense	Exon 2 of 4	NP_663625.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUC15	ENST00000529533.6	TSL:1 MANE Select	c.686C>T	p.Thr229Ile	missense	Exon 3 of 5	ENSP00000431983.1	A0A0A0MT67
	MUC15	ENST00000527569.1	TSL:1	c.686C>T	p.Thr229Ile	missense	Exon 3 of 4	ENSP00000431945.1	A0A0A0MTD6
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1447+5475G>A		intron	N/A	ENSP00000256737.3	Q9BYT9-1

Frequencies

GnomAD3 genomes AF: 0.619 AC: 93776 AN: 151506 Hom.: 29616 Cov.: 31

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.630

GnomAD2 exomes AF: 0.643 AC: 149330 AN: 232186 AF XY: 0.640

Gnomad AFR exome AF: 0.510

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.744

Gnomad NFE exome AF: 0.644

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.647 AC: 927123 AN: 1432174 Hom.: 302962 Cov.: 43 AF XY: 0.646 AC XY: 457898 AN XY: 709180

African (AFR) AF: 0.516 AC: 16749 AN: 32476

American (AMR) AF: 0.797 AC: 32780 AN: 41154

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 16105 AN: 24278

East Asian (EAS) AF: 0.406 AC: 16000 AN: 39376

South Asian (SAS) AF: 0.590 AC: 48343 AN: 81950

European-Finnish (FIN) AF: 0.736 AC: 38572 AN: 52392

Middle Eastern (MID) AF: 0.643 AC: 3574 AN: 5554

European-Non Finnish (NFE) AF: 0.654 AC: 717171 AN: 1096104

Other (OTH) AF: 0.642 AC: 37829 AN: 58890

GnomAD4 genome AF: 0.619 AC: 93797 AN: 151624 Hom.: 29615 Cov.: 31 AF XY: 0.625 AC XY: 46303 AN XY: 74124

African (AFR) AF: 0.519 AC: 21467 AN: 41382

American (AMR) AF: 0.726 AC: 11015 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2276 AN: 3466

East Asian (EAS) AF: 0.444 AC: 2273 AN: 5122

South Asian (SAS) AF: 0.571 AC: 2750 AN: 4814

European-Finnish (FIN) AF: 0.749 AC: 7915 AN: 10566

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.649 AC: 43979 AN: 67802

Other (OTH) AF: 0.624 AC: 1315 AN: 2108

Alfa AF: 0.633 Hom.: 107886

Bravo AF: 0.617

TwinsUK AF: 0.665 AC: 2467

ALSPAC AF: 0.662 AC: 2552

ESP6500AA AF: 0.515 AC: 2268

ESP6500EA AF: 0.648 AC: 5573

ExAC AF: 0.632 AC: 76628

Asia WGS AF: 0.504 AC: 1754 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.036
Sift	Benign	0.057	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.49	P
Vest4		0.076
MPC		0.17
ClinPred		0.037	T
GERP RS		2.1
Varity_R		0.13
gMVP		0.60
Mutation Taster		=44/56	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: rs15783; hg19: chr11-26586801; COSMIC: COSV55553509; COSMIC: COSV55553509;