NM_001135091.2:c.944C>T

Variant names:

• chr11-26561207-G-A
• rs759346265
• NM_001135091.2:c.944C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135091.2(MUC15):​c.944C>T​(p.Ala315Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A315E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MUC15 NM_001135091.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.00
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25971812).

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.944C>T	p.Ala315Val	missense	Exon 5 of 5	NP_001128563.1	A0A0A0MT67
	ANO3	NM_031418.4	MANE Select	c.1447+1428G>A		intron	N/A	NP_113606.2	Q9BYT9-1
	MUC15	NM_145650.4		c.863C>T	p.Ala288Val	missense	Exon 4 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.944C>T	p.Ala315Val	missense	Exon 5 of 5	ENSP00000431983.1	A0A0A0MT67
	MUC15	ENST00000527569.1	TSL:1	c.794C>T	p.Ala265Val	missense	Exon 4 of 4	ENSP00000431945.1	A0A0A0MTD6
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1447+1428G>A		intron	N/A	ENSP00000256737.3	Q9BYT9-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246038 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: 0.00

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456684 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724572

⚠️ 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: 33086

American (AMR) AF: 0.00 AC: 0 AN: 43946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.00 AC: 0 AN: 85416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109610

Other (OTH) AF: 0.0000166 AC: 1 AN: 60214

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L
PhyloP100		5.0
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.035
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.027	D
Polyphen		0.74	P
Vest4		0.14
MutPred		0.43		Loss of disorder (P = 0.1738)
MVP		0.21
MPC		0.15
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.45
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs759346265; hg19: chr11-26582754;