11-26559835-TACACACACACACACACACACACACACAC-TACACACACACACACACACACAC

Variant names:

• chr11-26559835-TACACAC-T
• rs71047866
• NM_001135091.2:c.*1224_*1229delGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001135091.2(MUC15):​c.*1224_*1229delGTGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 656,772 control chromosomes in the GnomAD database, including 72 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (61 hom., cov: 0)
  • Exomes 𝑓: 0.042 (11 hom.)
• Consequence: MUC15 NM_001135091.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.701
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 11-26559835-TACACAC-T is Benign according to our data. Variant chr11-26559835-TACACAC-T is described in ClinVar as Benign. ClinVar VariationId is 1240657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0564 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.*1224_*1229delGTGTGT		3_prime_UTR	Exon 5 of 5	NP_001128563.1	A0A0A0MT67
	ANO3	NM_031418.4	MANE Select	c.1447+91_1447+96delACACAC		intron	N/A	NP_113606.2	Q9BYT9-1
	MUC15	NM_145650.4		c.*1224_*1229delGTGTGT		3_prime_UTR	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.*1224_*1229delGTGTGT		3_prime_UTR	Exon 5 of 5	ENSP00000431983.1	A0A0A0MT67
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1447+91_1447+96delACACAC		intron	N/A	ENSP00000256737.3	Q9BYT9-1
	MUC15	ENST00000436318.6	TSL:5	c.*1224_*1229delGTGTGT		3_prime_UTR	Exon 4 of 4	ENSP00000416753.2	A0A0A0MT67

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2751 AN: 143924 Hom.: 60 Cov.: 0

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00476

Gnomad SAS AF: 0.0185

Gnomad FIN AF: 0.00158

Gnomad MID AF: 0.0135

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.0137

GnomAD4 exome AF: 0.0422 AC: 21663 AN: 512752 Hom.: 11 AF XY: 0.0427 AC XY: 11920 AN XY: 278852

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0591 AC: 920 AN: 15576

American (AMR) AF: 0.0306 AC: 1063 AN: 34782

Ashkenazi Jewish (ASJ) AF: 0.0320 AC: 475 AN: 14862

East Asian (EAS) AF: 0.0423 AC: 1285 AN: 30406

South Asian (SAS) AF: 0.0495 AC: 2552 AN: 51580

European-Finnish (FIN) AF: 0.0340 AC: 1243 AN: 36554

Middle Eastern (MID) AF: 0.0411 AC: 79 AN: 1920

European-Non Finnish (NFE) AF: 0.0431 AC: 12946 AN: 300606

Other (OTH) AF: 0.0416 AC: 1100 AN: 26466

⚠️ 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 AF: 0.0192 AC: 2768 AN: 144020 Hom.: 61 Cov.: 0 AF XY: 0.0191 AC XY: 1333 AN XY: 69904

African (AFR) AF: 0.0584 AC: 2246 AN: 38450

American (AMR) AF: 0.00856 AC: 123 AN: 14372

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3382

East Asian (EAS) AF: 0.00478 AC: 23 AN: 4816

South Asian (SAS) AF: 0.0190 AC: 84 AN: 4422

European-Finnish (FIN) AF: 0.00158 AC: 15 AN: 9522

Middle Eastern (MID) AF: 0.0146 AC: 4 AN: 274

European-Non Finnish (NFE) AF: 0.00370 AC: 244 AN: 65910

Other (OTH) AF: 0.0126 AC: 25 AN: 1986

Alfa AF: 0.00 Hom.: 143

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.70
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71047866; hg19: chr11-26581382;