chr6-75835967-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004999.4(MYO6):​c.553+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,583,646 control chromosomes in the GnomAD database, including 15,861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1365 hom., cov: 32)
Exomes 𝑓: 0.14 ( 14496 hom. )

Consequence

MYO6
NM_004999.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.663

Publications

9 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 6-75835967-T-C is Benign according to our data. Variant chr6-75835967-T-C is described in ClinVar as [Benign]. Clinvar id is 45164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO6NM_004999.4 linkc.553+11T>C intron_variant Intron 7 of 34 ENST00000369977.8 NP_004990.3 Q9UM54-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYO6ENST00000369977.8 linkc.553+11T>C intron_variant Intron 7 of 34 1 NM_004999.4 ENSP00000358994.3 Q9UM54-1

Frequencies

GnomAD3 genomes
AF:
0.130
AC:
19814
AN:
152130
Hom.:
1365
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.115
Gnomad AMI
AF:
0.110
Gnomad AMR
AF:
0.133
Gnomad ASJ
AF:
0.108
Gnomad EAS
AF:
0.0373
Gnomad SAS
AF:
0.0903
Gnomad FIN
AF:
0.131
Gnomad MID
AF:
0.140
Gnomad NFE
AF:
0.150
Gnomad OTH
AF:
0.146
GnomAD2 exomes
AF:
0.118
AC:
29722
AN:
251136
AF XY:
0.120
show subpopulations
Gnomad AFR exome
AF:
0.113
Gnomad AMR exome
AF:
0.0798
Gnomad ASJ exome
AF:
0.103
Gnomad EAS exome
AF:
0.0247
Gnomad FIN exome
AF:
0.134
Gnomad NFE exome
AF:
0.150
Gnomad OTH exome
AF:
0.134
GnomAD4 exome
AF:
0.138
AC:
197679
AN:
1431398
Hom.:
14496
Cov.:
26
AF XY:
0.137
AC XY:
97660
AN XY:
713956
show subpopulations
African (AFR)
AF:
0.110
AC:
3607
AN:
32866
American (AMR)
AF:
0.0833
AC:
3722
AN:
44692
Ashkenazi Jewish (ASJ)
AF:
0.106
AC:
2739
AN:
25938
East Asian (EAS)
AF:
0.0503
AC:
1989
AN:
39526
South Asian (SAS)
AF:
0.0926
AC:
7937
AN:
85700
European-Finnish (FIN)
AF:
0.139
AC:
7403
AN:
53390
Middle Eastern (MID)
AF:
0.107
AC:
610
AN:
5704
European-Non Finnish (NFE)
AF:
0.149
AC:
161742
AN:
1084214
Other (OTH)
AF:
0.134
AC:
7930
AN:
59368
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.456
Heterozygous variant carriers
0
7326
14651
21977
29302
36628
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
5626
11252
16878
22504
28130
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.130
AC:
19817
AN:
152248
Hom.:
1365
Cov.:
32
AF XY:
0.128
AC XY:
9535
AN XY:
74436
show subpopulations
African (AFR)
AF:
0.115
AC:
4789
AN:
41548
American (AMR)
AF:
0.133
AC:
2027
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.108
AC:
376
AN:
3468
East Asian (EAS)
AF:
0.0374
AC:
194
AN:
5186
South Asian (SAS)
AF:
0.0897
AC:
433
AN:
4826
European-Finnish (FIN)
AF:
0.131
AC:
1385
AN:
10594
Middle Eastern (MID)
AF:
0.137
AC:
40
AN:
292
European-Non Finnish (NFE)
AF:
0.150
AC:
10169
AN:
68010
Other (OTH)
AF:
0.144
AC:
304
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
900
1801
2701
3602
4502
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
214
428
642
856
1070
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.135
Hom.:
424
Bravo
AF:
0.128
Asia WGS
AF:
0.0680
AC:
236
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 19, 2009
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 24, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 37 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 22 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 37;C2931767:Autosomal dominant nonsyndromic hearing loss 22 Benign:1
Aug 10, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
3.3
DANN
Benign
0.52
PhyloP100
-0.66
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs12210963; hg19: chr6-76545684; COSMIC: COSV64119165; API