Genetic Variant NM_006790.3:c.149A>G (chr5-137870800-A-G) – ACMG Classification: Benign (-18 pts)

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

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]

MYOT links:

PKD2L2-DT (HGNC:55557): (PKD2L2 divergent transcript)

PKD2L2-DT links:

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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, 14 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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006790.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYOT	NM_006790.3	MANE Select	c.149A>G	p.Gln50Arg	missense	Exon 2 of 10	NP_006781.1	A0A0C4DFM5
MYOT	NM_001300911.2		c.-120-77A>G		intron	N/A	NP_001287840.1	B4DT68
MYOT	NM_001135940.2		c.-197+275A>G		intron	N/A	NP_001129412.1	Q9UBF9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYOT	ENST00000239926.9	TSL:1 MANE Select	c.149A>G	p.Gln50Arg	missense	Exon 2 of 10	ENSP00000239926.4	A0A0C4DFM5
MYOT	ENST00000968642.1		c.149A>G	p.Gln50Arg	missense	Exon 2 of 10	ENSP00000638701.1
MYOT	ENST00000968644.1		c.149A>G	p.Gln50Arg	missense	Exon 1 of 8	ENSP00000638703.1

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3532

AN:

152124

Hom.:

129

Cov.:

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.:

Cov.:

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:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000220

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00902

AC:

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

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

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.:

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:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68012

Other (OTH)

AF:

0.0152

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

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

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:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0742

AC:

327

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00772

AC:

937

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Myofibrillar myopathy 3 (4)

not provided (2)

Limb-Girdle Muscular Dystrophy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.012

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

PhyloP100

6.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.36

REVEL

Benign

0.046

Sift

Benign

0.042

Sift4G

Benign

0.57

Vest4

0.29

MVP

0.84

MPC

0.19

ClinPred

0.026

GERP RS

5.7

gMVP

0.53

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over