6-75890237-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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

Scores

2
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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/exons MANE Protein UniProt
MYO6NM_004999.4 linkuse as main transcriptc.2839C>T p.Arg947* stop_gained 26/35 ENST00000369977.8 NP_004990.3 Q9UM54-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYO6ENST00000369977.8 linkuse as main transcriptc.2839C>T p.Arg947* stop_gained 26/351 NM_004999.4 ENSP00000358994.3 Q9UM54-1

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
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 37 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaAug 18, 2023The 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
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteSep 23, 2024Based 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
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 30, 2022The 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
Vest4
0.60
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8

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

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

Other links and lift over

dbSNP: rs876657653; hg19: chr6-76599954; API