Genetic Variant MYO1A:p.Arg93* (chr12-57047675-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_005379.4(MYO1A):c.277C>T(p.Arg93*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,184 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 15 hom. )

Consequence

MYO1A
NM_005379.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 2.55

Publications

19 publications found

Variant links:

Genes affected

MYO1A (HGNC:7595): (myosin IA) This gene encodes a member of the myosin superfamily. The protein represents an unconventional myosin; it should not be confused with the conventional skeletal muscle myosin-1 (MYH1). Unconventional myosins contain the basic domains characteristic of conventional myosins and are further distinguished from class members by their tail domains. They function as actin-based molecular motors. Mutations in this gene have been associated with autosomal dominant deafness. Alternatively spliced variants have been found for this gene. [provided by RefSeq, Dec 2011]

MYO1A Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MYO1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 12-57047675-G-A is Benign according to our data. Variant chr12-57047675-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8146.

BS2

High AC in GnomAd4 at 366 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005379.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	NM_005379.4	MANE Select	c.277C>T	p.Arg93*	stop_gained	Exon 4 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.277C>T	p.Arg93*	stop_gained	Exon 5 of 29	NP_001242970.1	Q9UBC5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO1A	ENST00000300119.8	TSL:1 MANE Select	c.277C>T	p.Arg93*	stop_gained	Exon 4 of 28	ENSP00000300119.3	Q9UBC5
MYO1A	ENST00000442789.6	TSL:1	c.277C>T	p.Arg93*	stop_gained	Exon 5 of 29	ENSP00000393392.2	Q9UBC5
MYO1A	ENST00000907120.1		c.277C>T	p.Arg93*	stop_gained	Exon 4 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

366

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00290

AC:

727

AN:

250558

AF XY:

0.00292

show subpopulations

Gnomad AFR exome

AF:

0.000617

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00413

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00376

AC:

5498

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00366

AC XY:

2660

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00362

AC:

162

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00122

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.000568

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00307

AC:

164

AN:

53410

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00438

AC:

4875

AN:

1112002

Other (OTH)

AF:

0.00303

AC:

183

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

328

656

984

1312

1640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

186

372

558

744

930

<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:

0.00240

AC:

366

AN:

152322

Hom.:

Cov.:

AF XY:

0.00222

AC XY:

165

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41572

American (AMR)

AF:

0.00124

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00429

AC:

292

AN:

68040

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00397

Hom.:

Bravo

AF:

0.00271

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00320

AC:

389

EpiCase

AF:

0.00453

EpiControl

AF:

0.00344

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Autosomal dominant nonsyndromic hearing loss 48 (2)

not specified (2)

MYO1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.81

PhyloP100

2.6

Vest4

0.80

GERP RS

1.9

Mutation Taster

=134/66

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: 46

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