12-57048275-C-T

Variant names:

• chr12-57048275-C-T
• rs141658242
• NM_005379.4:c.49G>A

Variant summary

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

The NM_005379.4(MYO1A):​c.49G>A​(p.Glu17Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E17Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.52
• Publications: 0 publications found

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

ACMG classification

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO1A	NM_005379.4	c.49G>A	p.Glu17Lys	missense_variant	Exon 2 of 28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2	c.49G>A	p.Glu17Lys	missense_variant	Exon 3 of 29		NP_001242970.1
MYO1A	XM_047428876.1	c.49G>A	p.Glu17Lys	missense_variant	Exon 3 of 29		XP_047284832.1
MYO1A	XM_011538373.3	c.49G>A	p.Glu17Lys	missense_variant	Exon 2 of 25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8	c.49G>A	p.Glu17Lys	missense_variant	Exon 2 of 28	1	NM_005379.4	ENSP00000300119.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0050	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.50
MutPred		0.55		Loss of sheet (P = 0.0011);Loss of sheet (P = 0.0011);Loss of sheet (P = 0.0011);
MVP		0.93
MPC		0.48
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.74
gMVP		0.51
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs141658242; hg19: chr12-57442059;