12-57038505-G-C

Variant names:

• chr12-57038505-G-C
• rs571906190
• NM_005379.4:c.1667C>G

Variant summary

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

The NM_005379.4(MYO1A):​c.1667C>G​(p.Ser556Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S556F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.24
• 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.1667C>G	p.Ser556Cys	missense	Exon 17 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.1667C>G	p.Ser556Cys	missense	Exon 18 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.1667C>G	p.Ser556Cys	missense	Exon 17 of 28	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.1667C>G	p.Ser556Cys	missense	Exon 18 of 29	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.1799C>G	p.Ser600Cys	missense	Exon 17 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.46		Loss of disorder (P = 0.0143)
MVP		0.95
MPC		0.44
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.70
gMVP		0.27
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs571906190; hg19: chr12-57432289;