rs189900453

Positions:

• chr12-57037065-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_005379.4(MYO1A):​c.2082C>G​(p.Arg694=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (1 hom.)
• Consequence: MYO1A NM_005379.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.65

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-57037065-G-C is Benign according to our data. Variant chr12-57037065-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164587.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BP7: Synonymous conserved (PhyloP=1.65 with no splicing effect.
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.2082C>G	p.Arg694=	synonymous_variant	20/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.2082C>G	p.Arg694=	synonymous_variant	21/29
MYO1A	XM_047428876.1	c.2082C>G	p.Arg694=	synonymous_variant	21/29
MYO1A	XM_011538373.3	c.2082C>G	p.Arg694=	synonymous_variant	20/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.2082C>G	p.Arg694=	synonymous_variant	20/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.2082C>G	p.Arg694=	synonymous_variant	21/29	1		P1
MYO1A	ENST00000554234.5	c.1596C>G	p.Arg532=	synonymous_variant, NMD_transcript_variant	16/24	5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000266 AC: 67 AN: 251426 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00277

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461882 Hom.: 1 Cov.: 33 AF XY: 0.000111 AC XY: 81 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00310

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.0000982

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 06, 2016

- -

MYO1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

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). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 10, 2013

The Arg694Arg variant in exon 20 of MYO1A: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.1
DANN	Benign	0.74

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: rs189900453; hg19: chr12-57430849;