rs12297756

Variant names:

• chr12-57038825-C-G
• rs12297756
• NM_005379.4:c.1517G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-57038825-C-G
• chr12-57038825-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005379.4(MYO1A):​c.1517G>C​(p.Cys506Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,614,192 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (8 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.82
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010234833).
• BP6: Variant 12-57038825-C-G is Benign according to our data. Variant chr12-57038825-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00725 (1104/152306) while in subpopulation AFR AF = 0.0248 (1032/41560). AF 95% confidence interval is 0.0236. There are 17 homozygotes in GnomAd4. There are 528 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1104 AD gene.

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.1517G>C	p.Cys506Ser	missense	Exon 16 of 28	NP_005370.1	Q9UBC5
	MYO1A	NM_001256041.2		c.1517G>C	p.Cys506Ser	missense	Exon 17 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.1517G>C	p.Cys506Ser	missense	Exon 16 of 28	ENSP00000300119.3	Q9UBC5
	MYO1A	ENST00000442789.6	TSL:1	c.1517G>C	p.Cys506Ser	missense	Exon 17 of 29	ENSP00000393392.2	Q9UBC5
	MYO1A	ENST00000907120.1		c.1649G>C	p.Cys550Ser	missense	Exon 16 of 28	ENSP00000577179.1

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1102 AN: 152188 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00204 AC: 512 AN: 251108 AF XY: 0.00147

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000791 AC: 1157 AN: 1461886 Hom.: 8 Cov.: 32 AF XY: 0.000682 AC XY: 496 AN XY: 727244

African (AFR) AF: 0.0258 AC: 863 AN: 33480

American (AMR) AF: 0.00188 AC: 84 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: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5762

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1112012

Other (OTH) AF: 0.00189 AC: 114 AN: 60396

GnomAD4 genome AF: 0.00725 AC: 1104 AN: 152306 Hom.: 17 Cov.: 32 AF XY: 0.00709 AC XY: 528 AN XY: 74464

African (AFR) AF: 0.0248 AC: 1032 AN: 41560

American (AMR) AF: 0.00366 AC: 56 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00116 Hom.: 2

Bravo AF: 0.00835

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00233 AC: 283

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.69
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.22	N
PhyloP100		2.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.14
Sift	Benign	0.53	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.26		Gain of catalytic residue at C506 (P = 0.0456)
MVP		0.49
MPC		0.10
ClinPred		0.015	T
GERP RS		1.6
Varity_R		0.063
gMVP		0.30
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12297756; hg19: chr12-57432609; COSMIC: COSV99037935; COSMIC: COSV99037935;