12-57029508-A-G

Variant names:

Variant summary

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

The NM_005379.4(MYO1A):c.2804T>C(p.Ile935Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000206 in 1,614,166 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 3 hom. )

Consequence

MYO1A
NM_005379.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.76

Publications

3 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 12-57029508-A-G is Benign according to our data. Variant chr12-57029508-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164580.

BS2

High AC in GnomAd4 at 20 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	NM_005379.4	MANE Select	c.2804T>C	p.Ile935Thr	missense	Exon 26 of 28	NP_005370.1
	MYO1A	NM_001256041.2		c.2804T>C	p.Ile935Thr	missense	Exon 27 of 29	NP_001242970.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYO1A	ENST00000300119.8	TSL:1 MANE Select	c.2804T>C	p.Ile935Thr	missense	Exon 26 of 28	ENSP00000300119.3
MYO1A	ENST00000442789.6	TSL:1	c.2804T>C	p.Ile935Thr	missense	Exon 27 of 29	ENSP00000393392.2
MYO1A	ENST00000477864.1	TSL:2	n.367T>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000251

AC:

AN:

251314

AF XY:

0.000280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000213

AC:

312

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000383

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000190

AC:

211

AN:

1112010

Other (OTH)

AF:

0.000315

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000131

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41558

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000204

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO1A: BP4, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Uncertain:1

Apr 16, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Ile935Thr variant in MYO1A has been identified by our laboratory in one indi vidual with hearing loss; however this individual had an alternate genetic expla nation for their clinical features. This variant has not been reported in large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Ile935Thr variant is uncertain.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.73

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.67

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.6

PhyloP100

6.8

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.28

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.010

Polyphen

0.91

Vest4

0.57

MVP

0.56

MPC

0.34

ClinPred

0.47

GERP RS

4.5

Varity_R

0.25

gMVP

0.52

Mutation Taster

=69/31

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over