12-57047998-T-G

Position:

• chr12-57047998-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.390

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.221A>C	p.Lys74Thr	missense_variant	3/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.221A>C	p.Lys74Thr	missense_variant	4/29
MYO1A	XM_047428876.1	c.221A>C	p.Lys74Thr	missense_variant	4/29
MYO1A	XM_011538373.3	c.221A>C	p.Lys74Thr	missense_variant	3/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.221A>C	p.Lys74Thr	missense_variant	3/28	1	NM_005379.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 15, 2013

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.
Eigen	Benign	0.0060
Eigen_PC	Benign	0.00056
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.011	D;D;.
Polyphen		0.82	P;P;.
Vest4		0.60
MutPred		0.58		Loss of methylation at K74 (P = 0.0058);Loss of methylation at K74 (P = 0.0058);Loss of methylation at K74 (P = 0.0058);
MVP		0.71
MPC		0.11
ClinPred		0.62	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs727503323; hg19: chr12-57441782;