rs17546153

Positions:

• chr12-57041268-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005379.4(MYO1A):​c.1185T>C​(p.Phe395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 1,613,914 control chromosomes in the GnomAD database, including 1,315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (89 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1226 hom.)
• Consequence: MYO1A NM_005379.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.49

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 12-57041268-A-G is Benign according to our data. Variant chr12-57041268-A-G is described in ClinVar as [Benign]. Clinvar id is 45306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57041268-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.49 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.1185T>C	p.Phe395=	synonymous_variant	14/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.1185T>C	p.Phe395=	synonymous_variant	15/29
MYO1A	XM_047428876.1	c.1185T>C	p.Phe395=	synonymous_variant	15/29
MYO1A	XM_011538373.3	c.1185T>C	p.Phe395=	synonymous_variant	14/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.1185T>C	p.Phe395=	synonymous_variant	14/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.1185T>C	p.Phe395=	synonymous_variant	15/29	1		P1
MYO1A	ENST00000554234.5	c.699T>C	p.Phe233=	synonymous_variant, NMD_transcript_variant	10/24	5

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4517 AN: 152164 Hom.: 89 Cov.: 32

Gnomad AFR AF: 0.00640

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0417

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0356 AC: 8947 AN: 251328 Hom.: 224 AF XY: 0.0374 AC XY: 5084 AN XY: 135812

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0295

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0441

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0372 AC: 54366 AN: 1461632 Hom.: 1226 Cov.: 31 AF XY: 0.0373 AC XY: 27142 AN XY: 727120

Gnomad4 AFR exome AF: 0.00621

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0285

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0387

Gnomad4 OTH exome AF: 0.0409

GnomAD4 genome AF: 0.0296 AC: 4513 AN: 152282 Hom.: 89 Cov.: 32 AF XY: 0.0291 AC XY: 2167 AN XY: 74458

Gnomad4 AFR AF: 0.00635

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0229

Gnomad4 FIN AF: 0.0359

Gnomad4 NFE AF: 0.0417

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0417 Hom.: 119

Bravo AF: 0.0281

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0518

EpiControl AF: 0.0513

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Phe395Phe in Exon 14 of MYO1A: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 4.6% (325/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs17546153). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 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
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.3
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs17546153; hg19: chr12-57435052;