11-26561105-A-T

Position:

• chr11-26561105-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001135091.2(MUC15):​c.1046T>A​(p.Ile349Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUC15 NM_001135091.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUC15	NM_001135091.2	c.1046T>A	p.Ile349Asn	missense_variant	5/5	ENST00000529533.6	NP_001128563.1
ANO3	NM_031418.4	c.1447+1326A>T		intron_variant		ENST00000256737.8	NP_113606.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUC15	ENST00000529533.6	c.1046T>A	p.Ile349Asn	missense_variant	5/5	1	NM_001135091.2	ENSP00000431983.1
ANO3	ENST00000256737.8	c.1447+1326A>T		intron_variant		1	NM_031418.4	ENSP00000256737.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2024

The c.1046T>A (p.I349N) alteration is located in exon 5 (coding exon 4) of the MUC15 gene. This alteration results from a T to A substitution at nucleotide position 1046, causing the isoleucine (I) at amino acid position 349 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;D;D;.;.
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	.;.;L;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;.;D;.;.
Vest4		0.91
MutPred		0.32		.;.;Loss of stability (P = 0.0489);.;.;
MVP		0.42
MPC		0.19
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-26582652;