Genetic Variant MYO1A:p.Lys74Thr (chr12-57047998-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005379.4(MYO1A):c.221A>C(p.Lys74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MYO1A
NM_005379.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.390

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.221A>C	p.Lys74Thr	missense	Exon 3 of 28	NP_005370.1
	MYO1A	NM_001256041.2		c.221A>C	p.Lys74Thr	missense	Exon 4 of 29	NP_001242970.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYO1A	ENST00000300119.8	TSL:1 MANE Select	c.221A>C	p.Lys74Thr	missense	Exon 3 of 28	ENSP00000300119.3
MYO1A	ENST00000442789.6	TSL:1	c.221A>C	p.Lys74Thr	missense	Exon 4 of 29	ENSP00000393392.2
MYO1A	ENST00000433964.5	TSL:3	c.221A>C	p.Lys74Thr	missense	Exon 4 of 5	ENSP00000400991.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Lys74Thr variant in MYO1A has not been reported in individuals affected with hearing loss or in large population studies. Computational analyses (biochemica l amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not pr ovide strong support for or against an impact to the protein. In summary, additi onal data is needed to determine the clinical significance of this variant.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Benign

0.0060

Eigen_PC

Benign

0.00056

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.5

PhyloP100

0.39

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.34

Sift

Uncertain

0.011

Sift4G

Uncertain

0.011

Polyphen

0.82

Vest4

0.60

MutPred

0.58

Loss of methylation at K74 (P = 0.0058)

MVP

0.71

MPC

0.11

ClinPred

0.62

GERP RS

4.5

Varity_R

0.22

gMVP

0.66

Mutation Taster

=80/20

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over