chr5-137870800-A-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_006790.3(MYOT):​c.149A>G​(p.Gln50Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00435 in 1,614,130 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 129 hom., cov: 32)
Exomes 𝑓: 0.0024 ( 96 hom. )

Consequence

MYOT
NM_006790.3 missense

Scores

1
15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 6.34

Publications

10 publications found
Variant links:
Genes affected
MYOT (HGNC:12399): (myotilin) This gene encodes a cystoskeletal protein which plays a significant role in the stability of thin filaments during muscle contraction. This protein binds F-actin, crosslinks actin filaments, and prevents latrunculin A-induced filament disassembly. Mutations in this gene have been associated with limb-girdle muscular dystrophy and myofibrillar myopathies. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[provided by RefSeq, Oct 2008]
PKD2L2-DT (HGNC:55557): (PKD2L2 divergent transcript)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_006790.3
BP4
Computational evidence support a benign effect (MetaRNN=0.0017775893).
BP6
Variant 5-137870800-A-G is Benign according to our data. Variant chr5-137870800-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYOTNM_006790.3 linkc.149A>G p.Gln50Arg missense_variant Exon 2 of 10 ENST00000239926.9 NP_006781.1 Q9UBF9A0A0C4DFM5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYOTENST00000239926.9 linkc.149A>G p.Gln50Arg missense_variant Exon 2 of 10 1 NM_006790.3 ENSP00000239926.4 A0A0C4DFM5

Frequencies

GnomAD3 genomes
AF:
0.0232
AC:
3532
AN:
152124
Hom.:
129
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0799
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0105
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000456
Gnomad OTH
AF:
0.0153
GnomAD2 exomes
AF:
0.00612
AC:
1523
AN:
249012
AF XY:
0.00439
show subpopulations
Gnomad AFR exome
AF:
0.0804
Gnomad AMR exome
AF:
0.00451
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000341
Gnomad OTH exome
AF:
0.00310
GnomAD4 exome
AF:
0.00239
AC:
3489
AN:
1461888
Hom.:
96
Cov.:
31
AF XY:
0.00206
AC XY:
1498
AN XY:
727248
show subpopulations
African (AFR)
AF:
0.0768
AC:
2572
AN:
33480
American (AMR)
AF:
0.00543
AC:
243
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.000220
AC:
19
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00902
AC:
52
AN:
5768
European-Non Finnish (NFE)
AF:
0.000251
AC:
279
AN:
1112010
Other (OTH)
AF:
0.00535
AC:
323
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.468
Heterozygous variant carriers
0
225
450
676
901
1126
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
94
188
282
376
470
<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:
0.0232
AC:
3539
AN:
152242
Hom.:
129
Cov.:
32
AF XY:
0.0227
AC XY:
1689
AN XY:
74446
show subpopulations
African (AFR)
AF:
0.0798
AC:
3316
AN:
41528
American (AMR)
AF:
0.0105
AC:
160
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000456
AC:
31
AN:
68012
Other (OTH)
AF:
0.0152
AC:
32
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
164
328
493
657
821
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
34
68
102
136
170
<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:
0.00800
Hom.:
104
Bravo
AF:
0.0266
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.0742
AC:
327
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.00772
AC:
937
Asia WGS
AF:
0.00520
AC:
18
AN:
3478
EpiCase
AF:
0.000436
EpiControl
AF:
0.000711

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
Dec 16, 2013
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 19, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mar 24, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 20, 2021
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Myofibrillar myopathy 3 Benign:4
Jan 13, 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. -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 22, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 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. -

not provided Benign:2
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Limb-Girdle Muscular Dystrophy, Dominant Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
21
DANN
Benign
0.95
Eigen
Benign
-0.012
Eigen_PC
Benign
0.20
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.63
T
MetaRNN
Benign
0.0018
T
MetaSVM
Benign
-1.1
T
PhyloP100
6.3
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.36
N
REVEL
Benign
0.046
Sift
Benign
0.042
D
Sift4G
Benign
0.57
T
Vest4
0.29
MVP
0.84
MPC
0.19
ClinPred
0.026
T
GERP RS
5.7
gMVP
0.53
Mutation Taster
=95/5
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: rs34717730; hg19: chr5-137206489; API