rs727504567

Positions:

chr6-75828590-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PP1PM2_SupportingPS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_004999.4:c.238C>T (p.Arg80Ter) variant in MYO6 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/113330 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.002%) for PM2_Supporting. This variant has been reported in 2 families with teenage onset progressive sensorineural hearing loss, both displaying an autosomal dominant pattern of inheritance (PS4_Supporting; PMID:32143290, 33111345). The variant has been reported to segregate with hearing loss in 2 affected family members from 1 family (PP1; PMID:33111345). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PVS1, PM2_Supporting, PS4_Supporting, PP1). (VCEP specifications version 2.0.0; December 21, 2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA183381/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYO6
NM_004999.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 4.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO6	NM_004999.4 linkuse as main transcript	c.238C>T	p.Arg80Ter	stop_gained	4/35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8 linkuse as main transcript	c.238C>T	p.Arg80Ter	stop_gained	4/35	1	NM_004999.4	ENSP00000358994	A1	Q9UM54-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250810

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1429714

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151930

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74180

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 26, 2017

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jan 24, 2023

The NM_004999.4:c.238C>T (p.Arg80Ter) variant in MYO6 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0008% (1/113330 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<=0.002%) for PM2_Supporting. This variant has been reported in 2 families with teenage onset progressive sensorineural hearing loss, both displaying an autosomal dominant pattern of inheritance (PS4_Supporting; PMID: 32143290, 33111345). The variant has been reported to segregate with hearing loss in 2 affected family members from 1 family (PP1; PMID:33111345). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal dominant hearing loss, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: (PVS1, PM2_Supporting, PS4_Supporting, PP1). (VCEP specifications version 2.0.0; December 21, 2022) -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2020

Reported as a variant identified in the Deafness Variation Database, however, no additional information was provided (Sampaio-Silva et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29044474, 32143290, 33111345) -

Autosomal dominant nonsyndromic hearing loss 22

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Prof. Karen Avraham, Tel Aviv University

May 07, 2018

Dominant, teenage onset, progressive moderate high tone NSHL -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 05, 2013

The Arg80X variant in MYO6 has not been reported in individuals with hearing los s or in large population studies. This nonsense variant leads to a premature ter mination codon at position 80, which is predicted to lead to a truncated or abse nt protein. Nonsense variants in the MYO6 gene have been reported as disease cau sing variants in families with hearing loss. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinic al significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.89

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over