rs1045758

Positions:

• chr6-75915471-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004999.4(MYO6):​c.*459A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 169,082 control chromosomes in the GnomAD database, including 1,508 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1362 hom., cov: 33)
  • Exomes 𝑓: 0.12 (146 hom.)
• Consequence: MYO6 NM_004999.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-75915471-A-G is Benign according to our data. Variant chr6-75915471-A-G is described in ClinVar as [Benign]. Clinvar id is 358005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4	c.*459A>G		3_prime_UTR_variant	35/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.*459A>G		3_prime_UTR_variant	35/35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19751 AN: 152112 Hom.: 1362 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.0371

Gnomad SAS AF: 0.0901

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.123 AC: 2070 AN: 16852 Hom.: 146 Cov.: 0 AF XY: 0.123 AC XY: 1070 AN XY: 8724

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.0995

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.0206

Gnomad4 SAS exome AF: 0.0959

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.130 AC: 19751 AN: 152230 Hom.: 1362 Cov.: 33 AF XY: 0.128 AC XY: 9493 AN XY: 74428

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.0372

Gnomad4 SAS AF: 0.0895

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.143

Alfa AF: 0.137 Hom.: 315

Bravo AF: 0.128

Asia WGS AF: 0.0680 AC: 237 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.73
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs1045758; hg19: chr6-76625188;