11-26559835-TACACACACACACACACACACACACACAC-TACACACACACACACACACACACACACACAC

Variant names:

• chr11-26559835-T-TAC
• rs71047866
• NM_001135091.2:c.*1228_*1229dupGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001135091.2(MUC15):​c.*1228_*1229dupGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1958 hom., cov: 0)
  • Exomes 𝑓: 0.089 (33 hom.)
• Consequence: MUC15 NM_001135091.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.333
• 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 -16 ACMG points.

• BP6: Variant 11-26559835-T-TAC is Benign according to our data. Variant chr11-26559835-T-TAC is described in ClinVar as Benign. ClinVar VariationId is 1228643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.196 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.*1228_*1229dupGT		3_prime_UTR	Exon 5 of 5	NP_001128563.1	A0A0A0MT67
	ANO3	NM_031418.4	MANE Select	c.1447+95_1447+96dupAC		intron	N/A	NP_113606.2	Q9BYT9-1
	MUC15	NM_145650.4		c.*1228_*1229dupGT		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.*1228_*1229dupGT		3_prime_UTR	Exon 5 of 5	ENSP00000431983.1	A0A0A0MT67
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1447+95_1447+96dupAC		intron	N/A	ENSP00000256737.3	Q9BYT9-1
	MUC15	ENST00000436318.6	TSL:5	c.*1228_*1229dupGT		3_prime_UTR	Exon 4 of 4	ENSP00000416753.2	A0A0A0MT67

Frequencies

GnomAD3 genomes AF: 0.162 AC: 23321 AN: 143784 Hom.: 1960 Cov.: 0

Gnomad AFR AF: 0.0766

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.167

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.0889 AC: 45280 AN: 509604 Hom.: 33 Cov.: 0 AF XY: 0.0902 AC XY: 25001 AN XY: 277064

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

African (AFR) AF: 0.0350 AC: 549 AN: 15668

American (AMR) AF: 0.0827 AC: 2861 AN: 34586

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 1525 AN: 14728

East Asian (EAS) AF: 0.0806 AC: 2445 AN: 30324

South Asian (SAS) AF: 0.0989 AC: 5062 AN: 51166

European-Finnish (FIN) AF: 0.137 AC: 4939 AN: 36080

Middle Eastern (MID) AF: 0.0779 AC: 149 AN: 1912

European-Non Finnish (NFE) AF: 0.0850 AC: 25405 AN: 298848

Other (OTH) AF: 0.0892 AC: 2345 AN: 26292

⚠️ 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: 0.162 AC: 23315 AN: 143882 Hom.: 1958 Cov.: 0 AF XY: 0.166 AC XY: 11572 AN XY: 69834

African (AFR) AF: 0.0765 AC: 2942 AN: 38442

American (AMR) AF: 0.189 AC: 2718 AN: 14350

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 783 AN: 3380

East Asian (EAS) AF: 0.153 AC: 737 AN: 4804

South Asian (SAS) AF: 0.207 AC: 912 AN: 4404

European-Finnish (FIN) AF: 0.257 AC: 2446 AN: 9508

Middle Eastern (MID) AF: 0.162 AC: 44 AN: 272

European-Non Finnish (NFE) AF: 0.186 AC: 12228 AN: 65856

Other (OTH) AF: 0.157 AC: 312 AN: 1986

Alfa AF: 0.179 Hom.: 143

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Dystonia 24 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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;