rs143613424

chr12-57036354-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_005379.4(MYO1A):c.2302C>T(p.Arg768Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00104 in 1,613,788 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.60

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19470915).
• BP6: Variant 12-57036354-G-A is Benign according to our data. Variant chr12-57036354-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 45309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57036354-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.2302C>T	p.Arg768Trp	missense_variant	22/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.2302C>T	p.Arg768Trp	missense_variant	23/29
MYO1A	XM_047428876.1	c.2302C>T	p.Arg768Trp	missense_variant	23/29
MYO1A	XM_011538373.3	c.2302C>T	p.Arg768Trp	missense_variant	22/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.2302C>T	p.Arg768Trp	missense_variant	22/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.2302C>T	p.Arg768Trp	missense_variant	23/29	1		P1
MYO1A	ENST00000554234.5	c.1816C>T	p.Arg606Trp	missense_variant, NMD_transcript_variant	18/24	5

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000828 AC: 208 AN: 251144 Hom.: 1 AF XY: 0.000906 AC XY: 123 AN XY: 135722

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00154

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00109 AC: 1596 AN: 1461496 Hom.: 2 Cov.: 32 AF XY: 0.00113 AC XY: 822 AN XY: 727052

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00187

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74480

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000931 Hom.: 1

Bravo AF: 0.000604

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00105 AC: 128

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 29, 2012	Arg768Trp in exon 22 of MYO1A: This variant is not expected to have clinical sig nificance because it has been identified in 0.2% (16/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS/; dbSNP rs143613424) -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	0.016
Eigen_PC	Benign	0.0071
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	D;D
Vest4		0.74
MVP		0.89
MPC		0.46
ClinPred		0.22	T
GERP RS		3.9
Varity_R		0.23
gMVP		0.41

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: rs143613424; hg19: chr12-57430138; COSMIC: COSV55653909; COSMIC: COSV55653909;