6-75890237-C-T

Variant names:

• chr6-75890237-C-T
• rs876657653
• NM_004999.4:c.2839C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004999.4(MYO6):​c.2839C>T​(p.Arg947*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYO6 NM_004999.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.09
• Publications: 2 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-75890237-C-T is Pathogenic according to our data. Variant chr6-75890237-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO6	NM_004999.4	c.2839C>T	p.Arg947*	stop_gained	Exon 26 of 35	ENST00000369977.8	NP_004990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO6	ENST00000369977.8	c.2839C>T	p.Arg947*	stop_gained	Exon 26 of 35	1	NM_004999.4	ENSP00000358994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460506 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726688

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110868

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 37 Pathogenic:1

Aug 18, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYO6 c.2839C>T (p.Arg947Ter) nonsense variant results in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not, to our knowledge, been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant was identified in a homozygous state. Based on the available evidence, the c.2839C>T (p.Arg947Ter) variant is classified as pathogenic for nonsyndromic hearing loss. -

Autosomal dominant nonsyndromic hearing loss 22 Pathogenic:1

Sep 23, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness 22 with or without hypertrophic cardiomyopathy (MIM#606346) and deafness 37 (MIM#607821) (DECIPHER; PMID: 30582396). Dominant-negative has also been suggested as mechanisms of disease associated with missense variants in this gene (PMID: 30582396). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least ten NMD-predicted variants that have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified once as likely pathogenic by a clinical diagnostic laboratory (ClinVar). This variant has also been reported in one Japanese family with autosomal dominant hearing loss and classified as likely pathogenic (PMID: 32143290). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Rare genetic deafness Pathogenic:1

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg947X variant in MYO6 has been reported in one individual with progressive hearing loss that onset in the early 20s (Oka 2020 PMID: 32143290) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 947, which is predicted to lead to a truncated or absent protein. Truncating or loss-of-function variants in the MYO6 gene have been associated with autosomal recessive hearing loss as well as autosomal dominant hearing loss. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg947X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2_P. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		3.1
Vest4		0.60
GERP RS		5.1
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs876657653; hg19: chr6-76599954;