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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	NM_005379.4	MANE Select	c.49G>A	p.Glu17Lys	missense	Exon 2 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.49G>A	p.Glu17Lys	missense	Exon 3 of 29	NP_001242970.1	Q9UBC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO1A	ENST00000300119.8	TSL:1 MANE Select	c.49G>A	p.Glu17Lys	missense	Exon 2 of 28	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.49G>A	p.Glu17Lys	missense	Exon 3 of 29	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.49G>A	p.Glu17Lys	missense	Exon 2 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.50
MutPred		0.55		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;