rs11756446

Positions:

• chr6-75866573-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004999.4(MYO6):​c.1722C>T​(p.Asp574=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 1,613,280 control chromosomes in the GnomAD database, including 2,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (211 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2731 hom.)
• Consequence: MYO6 NM_004999.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.40

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 6-75866573-C-T is Benign according to our data. Variant chr6-75866573-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75866573-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.1722C>T	p.Asp574=	synonymous_variant	17/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.1722C>T	p.Asp574=	synonymous_variant	17/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6527 AN: 152040 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0587

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.0430

GnomAD3 exomes AF: 0.0509 AC: 12806 AN: 251428 Hom.: 365 AF XY: 0.0538 AC XY: 7316 AN XY: 135882

Gnomad AFR exome AF: 0.00935

Gnomad AMR exome AF: 0.0248

Gnomad ASJ exome AF: 0.0713

Gnomad EAS exome AF: 0.0192

Gnomad SAS exome AF: 0.0661

Gnomad FIN exome AF: 0.0642

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0551

GnomAD4 exome AF: 0.0580 AC: 84709 AN: 1461124 Hom.: 2731 Cov.: 31 AF XY: 0.0585 AC XY: 42558 AN XY: 726882

Gnomad4 AFR exome AF: 0.00863

Gnomad4 AMR exome AF: 0.0259

Gnomad4 ASJ exome AF: 0.0690

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.0655

Gnomad4 FIN exome AF: 0.0637

Gnomad4 NFE exome AF: 0.0613

Gnomad4 OTH exome AF: 0.0573

GnomAD4 genome AF: 0.0429 AC: 6530 AN: 152156 Hom.: 211 Cov.: 32 AF XY: 0.0433 AC XY: 3218 AN XY: 74378

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.0329

Gnomad4 ASJ AF: 0.0729

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.0591

Gnomad4 FIN AF: 0.0612

Gnomad4 NFE AF: 0.0593

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0545 Hom.: 128

Bravo AF: 0.0395

Asia WGS AF: 0.0420 AC: 144 AN: 3478

EpiCase AF: 0.0561

EpiControl AF: 0.0602

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2009	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 22 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.59
CADD	Benign	0.32
DANN	Benign	0.83

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: rs11756446; hg19: chr6-76576290;