11-26559835-TACACACACACACACACACACACACACAC-TACACACACACACACACACACACACACACACAC

Variant names:

• chr11-26559835-T-TACAC
• rs71047866
• NM_001135091.2:c.*1226_*1229dupGTGT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001135091.2(MUC15):​c.*1226_*1229dupGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (11 hom., cov: 0)
  • Exomes 𝑓: 0.0067 (0 hom.)
• Consequence: MUC15 NM_001135091.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 11-26559835-T-TACAC is Benign according to our data. Variant chr11-26559835-T-TACAC is described in ClinVar as Likely_benign. ClinVar VariationId is 1195324.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.*1226_*1229dupGTGT		3_prime_UTR	Exon 5 of 5	NP_001128563.1	A0A0A0MT67
	ANO3	NM_031418.4	MANE Select	c.1447+93_1447+96dupACAC		intron	N/A	NP_113606.2	Q9BYT9-1
	MUC15	NM_145650.4		c.*1226_*1229dupGTGT		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.*1226_*1229dupGTGT		3_prime_UTR	Exon 5 of 5	ENSP00000431983.1	A0A0A0MT67
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1447+93_1447+96dupACAC		intron	N/A	ENSP00000256737.3	Q9BYT9-1
	MUC15	ENST00000436318.6	TSL:5	c.*1226_*1229dupGTGT		3_prime_UTR	Exon 4 of 4	ENSP00000416753.2	A0A0A0MT67

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1688 AN: 143980 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.00693

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00766

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00761

GnomAD4 exome AF: 0.00672 AC: 3471 AN: 516308 Hom.: 0 Cov.: 0 AF XY: 0.00682 AC XY: 1916 AN XY: 280814

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

African (AFR) AF: 0.00413 AC: 65 AN: 15742

American (AMR) AF: 0.00604 AC: 211 AN: 34910

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 151 AN: 14960

East Asian (EAS) AF: 0.00703 AC: 215 AN: 30602

South Asian (SAS) AF: 0.00696 AC: 362 AN: 52014

European-Finnish (FIN) AF: 0.0111 AC: 406 AN: 36740

Middle Eastern (MID) AF: 0.00725 AC: 14 AN: 1932

European-Non Finnish (NFE) AF: 0.00615 AC: 1861 AN: 302746

Other (OTH) AF: 0.00698 AC: 186 AN: 26662

⚠️ 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: 0.0117 AC: 1689 AN: 144076 Hom.: 11 Cov.: 0 AF XY: 0.0124 AC XY: 868 AN XY: 69934

African (AFR) AF: 0.00694 AC: 267 AN: 38472

American (AMR) AF: 0.00974 AC: 140 AN: 14376

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 77 AN: 3380

East Asian (EAS) AF: 0.00768 AC: 37 AN: 4816

South Asian (SAS) AF: 0.0108 AC: 48 AN: 4424

European-Finnish (FIN) AF: 0.0207 AC: 197 AN: 9536

Middle Eastern (MID) AF: 0.0109 AC: 3 AN: 274

European-Non Finnish (NFE) AF: 0.0137 AC: 905 AN: 65924

Other (OTH) AF: 0.00755 AC: 15 AN: 1988

Alfa AF: 0.00370 Hom.: 143

ClinVar

ClinVar submissions

Significance: Likely 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		-0.33
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;