11-26559835-TACACACACACACACACACACACACACAC-TACACACACACACACACAC

Variant names:

• chr11-26559835-TACACACACAC-T
• rs71047866
• NM_001135091.2:c.*1220_*1229delGTGTGTGTGT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001135091.2(MUC15):​c.*1220_*1229delGTGTGTGTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 659,994 control chromosomes in the GnomAD database, including 8 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 0)
  • Exomes 𝑓: 0.019 (4 hom.)
• Consequence: MUC15 NM_001135091.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 4 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.*1220_*1229delGTGTGTGTGT		3_prime_UTR	Exon 5 of 5	NP_001128563.1	A0A0A0MT67
	ANO3	NM_031418.4	MANE Select	c.1447+87_1447+96delACACACACAC		intron	N/A	NP_113606.2	Q9BYT9-1
	MUC15	NM_145650.4		c.*1220_*1229delGTGTGTGTGT		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.*1220_*1229delGTGTGTGTGT		3_prime_UTR	Exon 5 of 5	ENSP00000431983.1	A0A0A0MT67
	ANO3	ENST00000256737.8	TSL:1 MANE Select	c.1447+87_1447+96delACACACACAC		intron	N/A	ENSP00000256737.3	Q9BYT9-1
	MUC15	ENST00000436318.6	TSL:5	c.*1220_*1229delGTGTGTGTGT		3_prime_UTR	Exon 4 of 4	ENSP00000416753.2	A0A0A0MT67

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 759 AN: 143980 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00571

Gnomad ASJ AF: 0.0272

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.000451

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000940

Gnomad OTH AF: 0.00457

GnomAD4 exome AF: 0.0190 AC: 9818 AN: 515918 Hom.: 4 AF XY: 0.0189 AC XY: 5302 AN XY: 280616

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

African (AFR) AF: 0.0227 AC: 358 AN: 15748

American (AMR) AF: 0.0122 AC: 426 AN: 34934

Ashkenazi Jewish (ASJ) AF: 0.0376 AC: 562 AN: 14964

East Asian (EAS) AF: 0.0251 AC: 769 AN: 30598

South Asian (SAS) AF: 0.0127 AC: 663 AN: 52008

European-Finnish (FIN) AF: 0.0108 AC: 398 AN: 36766

Middle Eastern (MID) AF: 0.0216 AC: 42 AN: 1940

European-Non Finnish (NFE) AF: 0.0199 AC: 6026 AN: 302336

Other (OTH) AF: 0.0216 AC: 574 AN: 26624

⚠️ 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: 0.00527 AC: 759 AN: 144076 Hom.: 4 Cov.: 0 AF XY: 0.00566 AC XY: 396 AN XY: 69932

African (AFR) AF: 0.0115 AC: 443 AN: 38472

American (AMR) AF: 0.00577 AC: 83 AN: 14380

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 92 AN: 3382

East Asian (EAS) AF: 0.0143 AC: 69 AN: 4812

South Asian (SAS) AF: 0.000226 AC: 1 AN: 4424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000940 AC: 62 AN: 65928

Other (OTH) AF: 0.00453 AC: 9 AN: 1986

Alfa AF: 0.00 Hom.: 143

ClinVar

Not reported in ClinVar

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;