rs876657911

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_004999.4(MYO6):​c.3610C>T​(p.Arg1204Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,888 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MYO6
NM_004999.4 missense

Scores

11
5
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 0.973
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 Uncertain_significance. Variant got 5 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.943
PP5
Variant 6-75914233-C-T is Pathogenic according to our data. Variant chr6-75914233-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228996.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}. Variant chr6-75914233-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-75914233-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO6NM_004999.4 linkc.3610C>T p.Arg1204Trp missense_variant Exon 34 of 35 ENST00000369977.8 NP_004990.3 Q9UM54-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYO6ENST00000369977.8 linkc.3610C>T p.Arg1204Trp missense_variant Exon 34 of 35 1 NM_004999.4 ENSP00000358994.3 Q9UM54-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251452
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000629
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxOct 28, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18348273, 18212818, 23635807, 12687499, 24123792, 28000701, 33710140, 23340379, 38400873, 35661827, 39019031) -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 31, 2024This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1204 of the MYO6 protein (p.Arg1204Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with deafness (PMID: 23340379, 33710140). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 04, 2015Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1204Tr p variant in MYO6 has been reported in 1 Dutch individual with hearing loss and segregated with disease in 9 affected family members (Oonk 2013). However, thre e unaffected individuals under or around the reported mean age of onset (38 yrs) also carried the variant, and the proband in this family had a different phenot ype than the other 9 affected family members with a much earlier age of onset an d more severe hearing impairment. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that t he Arg1204Trp variant may impact the protein, though this information is not pre dictive enough to determine pathogenicity. In summary, while there is some suspi cion for a pathogenic role, the clinical significance of this variant is uncerta in due to inconsistencies in the segregation and age of onset reported for the D utch family described above. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.47
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
T;.;.;.;T;T
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Pathogenic
1.0
D;.;D;D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-7.2
.;D;D;.;D;.
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
.;D;D;.;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
.;D;D;D;.;.
Vest4
0.83
MVP
0.98
MPC
0.95
ClinPred
0.99
D
GERP RS
3.9
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs876657911; hg19: chr6-76623950; API