rs727504567

Positions:

• chr6-75828590-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1 PM2_Supporting PS4_Supporting PVS1

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
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 4.46

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 Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO6	NM_004999.4	c.238C>T	p.Arg80Ter	stop_gained	4/35	ENST00000369977.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO6	ENST00000369977.8	c.238C>T	p.Arg80Ter	stop_gained	4/35	1	NM_004999.4	A1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 32

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: 1 AN: 250810 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135606

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: 2 AN: 1429714 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 713240

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: 1 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74180

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: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

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	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
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

Other links and lift over

dbSNP: rs727504567; hg19: chr6-76538307;