Genetic Variant MYO1A:p.Leu228Met (chr12-57044168-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005379.4(MYO1A):c.682C>A(p.Leu228Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L228V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MYO1A
NM_005379.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.39

Publications

0 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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MYO1A	NM_005379.4 link	c.682C>A	p.Leu228Met	missense_variant	Exon 9 of 28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2 link	c.682C>A	p.Leu228Met	missense_variant	Exon 10 of 29		NP_001242970.1
MYO1A	XM_047428876.1 link	c.682C>A	p.Leu228Met	missense_variant	Exon 10 of 29		XP_047284832.1
MYO1A	XM_011538373.3 link	c.682C>A	p.Leu228Met	missense_variant	Exon 9 of 25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYO1A	ENST00000300119.8 link	c.682C>A	p.Leu228Met	missense_variant	Exon 9 of 28	1	NM_005379.4	ENSP00000300119.3
MYO1A	ENST00000442789.6 link	c.682C>A	p.Leu228Met	missense_variant	Exon 10 of 29	1		ENSP00000393392.2
MYO1A	ENST00000554234.5 link	n.196C>A		non_coding_transcript_exon_variant	Exon 5 of 24	5		ENSP00000451033.1
MYO1A	ENST00000492945.5 link	c.-20-810C>A		intron_variant	Intron 2 of 4	4		ENSP00000452229.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

D;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.0

.;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

6.4

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.8

N;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0060

D;D

Vest4

0.55

ClinPred

0.97

GERP RS

3.0

Varity_R

0.57

gMVP

0.45

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over