rs121909305

Positions:

• chr12-57047675-G-A
• chr12-57047675-G-C
• chr12-57047675-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005379.4(MYO1A):​c.277C>T​(p.Arg93*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,184 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (15 hom.)
• Consequence: MYO1A NM_005379.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 2.55

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 12-57047675-G-A is Benign according to our data. Variant chr12-57047675-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8146.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}. Variant chr12-57047675-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO1A	NM_005379.4	c.277C>T	p.Arg93*	stop_gained	4/28	ENST00000300119.8	NP_005370.1
MYO1A	NM_001256041.2	c.277C>T	p.Arg93*	stop_gained	5/29		NP_001242970.1
MYO1A	XM_047428876.1	c.277C>T	p.Arg93*	stop_gained	5/29		XP_047284832.1
MYO1A	XM_011538373.3	c.277C>T	p.Arg93*	stop_gained	4/25		XP_011536675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO1A	ENST00000300119.8	c.277C>T	p.Arg93*	stop_gained	4/28	1	NM_005379.4	ENSP00000300119.3

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 366 AN: 152204 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00290 AC: 727 AN: 250558 Hom.: 7 AF XY: 0.00292 AC XY: 395 AN XY: 135466

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00413

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00376 AC: 5498 AN: 1461862 Hom.: 15 Cov.: 32 AF XY: 0.00366 AC XY: 2660 AN XY: 727230

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00362

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.00307

Gnomad4 NFE exome AF: 0.00438

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.00240 AC: 366 AN: 152322 Hom.: 3 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74474

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00429

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00381 Hom.: 7

Bravo AF: 0.00271

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00320 AC: 389

EpiCase AF: 0.00453

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	This variant is associated with the following publications: (PMID: 29308629, 27759032, 25262649, 24616153, 26086970, 12736868, 25525159) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	MYO1A: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 19, 2013	Variant classified as Uncertain Significance - Favor Benign. The Arg93X variant in MYO1A has been reported in 1 Italian individual with moderately-severe sensor ineural hearing loss; however it was also present in this individual?s mother wh o reported normal hearing (Donaudy 2003). It has also been identified in 0.5% (4 5/8600) of European American chromosomes and 0.07% (3/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/), as well as in 0.8% (1/120) of Colombian chromosomes by the 1000 Genomes P roject (dbSNP rs121909305). This nonsense variant leads to a premature terminati on codon at position 93, which is predicted to lead to a truncated or absent pro tein. However, it is unclear whether loss of function variants in MYO1A are caus ative for hearing loss. In summary, although we cannot rule out that this varian t may be causative for dominant hearing loss with low penetrance and/or variable expressivity, based upon its high frequency in the general population and its p resence in an unaffected family member of an individual with hearing loss, we wo uld lean towards a more likely benign role. -

Autosomal dominant nonsyndromic hearing loss 48 Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	May 10, 2016	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -

MYO1A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.80
GERP RS		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 46

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909305; hg19: chr12-57441459; COSMIC: COSV55652631; COSMIC: COSV55652631;