rs13211391

Variant names:

• chr6-75885917-C-A
• rs13211391
• NM_004999.4:c.2417-87C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004999.4(MYO6):​c.2417-87C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 780,340 control chromosomes in the GnomAD database, including 8,131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1849 hom., cov: 32)
  • Exomes 𝑓: 0.14 (6282 hom.)
• Consequence: MYO6 NM_004999.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.453
• Publications: 1 publications found

Genes affected

MYO6 (HGNC:7605): (myosin VI) This gene encodes a reverse-direction motor protein that moves toward the minus end of actin filaments and plays a role in intracellular vesicle and organelle transport. The protein consists of a motor domain containing an ATP- and an actin-binding site and a globular tail which interacts with other proteins. This protein maintains the structural integrity of inner ear hair cells and mutations in this gene cause non-syndromic autosomal dominant and recessive hearing loss. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

MYO6 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 22

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, G2P
• autosomal recessive nonsyndromic hearing loss 37

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-75885917-C-A is Benign according to our data. Variant chr6-75885917-C-A is described in ClinVar as Benign. ClinVar VariationId is 674705.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.2417-87C>A		intron_variant	Intron 23 of 34	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.2417-87C>A		intron_variant	Intron 23 of 34	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22873 AN: 151952 Hom.: 1850 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0374

Gnomad SAS AF: 0.0906

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.156

GnomAD4 exome AF: 0.136 AC: 85695 AN: 628270 Hom.: 6282 AF XY: 0.133 AC XY: 44462 AN XY: 333158

African (AFR) AF: 0.188 AC: 2901 AN: 15426

American (AMR) AF: 0.0941 AC: 2596 AN: 27598

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2005 AN: 19084

East Asian (EAS) AF: 0.0554 AC: 1753 AN: 31640

South Asian (SAS) AF: 0.0922 AC: 5243 AN: 56882

European-Finnish (FIN) AF: 0.138 AC: 6412 AN: 46446

Middle Eastern (MID) AF: 0.116 AC: 284 AN: 2446

European-Non Finnish (NFE) AF: 0.151 AC: 59988 AN: 396718

Other (OTH) AF: 0.141 AC: 4513 AN: 32030

GnomAD4 genome AF: 0.150 AC: 22883 AN: 152070 Hom.: 1849 Cov.: 32 AF XY: 0.148 AC XY: 10970 AN XY: 74336

African (AFR) AF: 0.186 AC: 7722 AN: 41466

American (AMR) AF: 0.139 AC: 2129 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 376 AN: 3468

East Asian (EAS) AF: 0.0374 AC: 194 AN: 5182

South Asian (SAS) AF: 0.0901 AC: 434 AN: 4818

European-Finnish (FIN) AF: 0.131 AC: 1380 AN: 10566

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10182 AN: 67970

Other (OTH) AF: 0.154 AC: 324 AN: 2110

Alfa AF: 0.153 Hom.: 275

Bravo AF: 0.152

Asia WGS AF: 0.0730 AC: 256 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.35
DANN	Benign	0.42
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs13211391; hg19: chr6-76595634;