rs33962952

chr12-57037618-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005379.4(MYO1A):c.1985G>A(p.Gly662Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,614,020 control chromosomes in the GnomAD database, including 869 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (68 hom., cov: 32)
  • Exomes 𝑓: 0.029 (801 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -1.80

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009011149).
• BP6: Variant 12-57037618-C-T is Benign according to our data. Variant chr12-57037618-C-T is described in ClinVar as [Benign]. Clinvar id is 8150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57037618-C-T is described in Lovd as [Benign]. Variant chr12-57037618-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.1985G>A	p.Gly662Glu	missense_variant	19/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.1985G>A	p.Gly662Glu	missense_variant	20/29
MYO1A	XM_047428876.1	c.1985G>A	p.Gly662Glu	missense_variant	20/29
MYO1A	XM_011538373.3	c.1985G>A	p.Gly662Glu	missense_variant	19/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.1985G>A	p.Gly662Glu	missense_variant	19/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.1985G>A	p.Gly662Glu	missense_variant	20/29	1		P1
MYO1A	ENST00000554234.5	c.1499G>A	p.Gly500Glu	missense_variant, NMD_transcript_variant	15/24	5

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3647 AN: 152150 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00473

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0336

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0298 AC: 7473 AN: 250634 Hom.: 169 AF XY: 0.0313 AC XY: 4246 AN XY: 135530

Gnomad AFR exome AF: 0.00396

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0237

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0349

Gnomad OTH exome AF: 0.0416

GnomAD4 exome AF: 0.0289 AC: 42190 AN: 1461752 Hom.: 801 Cov.: 32 AF XY: 0.0292 AC XY: 21216 AN XY: 727176

Gnomad4 AFR exome AF: 0.00481

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.0319

Gnomad4 NFE exome AF: 0.0291

Gnomad4 OTH exome AF: 0.0325

GnomAD4 genome AF: 0.0239 AC: 3644 AN: 152268 Hom.: 68 Cov.: 32 AF XY: 0.0236 AC XY: 1757 AN XY: 74454

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0336

Gnomad4 NFE AF: 0.0326

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0348 Hom.: 155

Bravo AF: 0.0226

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0293 AC: 113

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.0377 AC: 324

ExAC AF: 0.0300 AC: 3642

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0415

EpiControl AF: 0.0419

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 09, 2013	This variant has been identified in 3.8% (324/8600) of European American chromos omes from a broad population by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs33962952) -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 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. -

Autosomal dominant nonsyndromic hearing loss 48 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

May 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	1.7
Dann	Benign	0.57
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.087	N
MetaRNN	Benign	0.0090	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N
MutationTaster	Benign	0.097	A;A;A
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.064
Sift	Benign	1.0	T;T
Sift4G	Benign	0.94	T;T
Polyphen		0.0010	B;B
Vest4		0.15
MPC		0.11
ClinPred		0.0037	T
GERP RS		-1.1
Varity_R		0.084
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs33962952; hg19: chr12-57431402;