rs114674819

chr12-57044191-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005379.4(MYO1A):c.659G>A(p.Arg220Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,614,050 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R220W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (2 hom.)
• Consequence: MYO1A NM_005379.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.231

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052224696).
• BP6: Variant 12-57044191-C-T is Benign according to our data. Variant chr12-57044191-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 164597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 100 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO1A	NM_005379.4	c.659G>A	p.Arg220Gln	missense_variant	9/28	ENST00000300119.8
MYO1A	NM_001256041.2	c.659G>A	p.Arg220Gln	missense_variant	10/29
MYO1A	XM_047428876.1	c.659G>A	p.Arg220Gln	missense_variant	10/29
MYO1A	XM_011538373.3	c.659G>A	p.Arg220Gln	missense_variant	9/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO1A	ENST00000300119.8	c.659G>A	p.Arg220Gln	missense_variant	9/28	1	NM_005379.4	P1
MYO1A	ENST00000442789.6	c.659G>A	p.Arg220Gln	missense_variant	10/29	1		P1
MYO1A	ENST00000492945.5	c.-20-833G>A		intron_variant		4
MYO1A	ENST00000554234.5	c.173G>A	p.Arg58Gln	missense_variant, NMD_transcript_variant	5/24	5

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251146 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135762

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461712 Hom.: 2 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 727172

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74490

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000210 Hom.: 0

Bravo AF: 0.000733

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 13, 2013

The Arg220Gln variant in MYO1A: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of note, mouse lemur, kangaroo rat, hedgehog, shrew, elephant, and sloth have a glu tamine (Gln) at this position. In addition, this variant has been identified in 0.2% (9/4406) of African American chromosomes by the NHLBI Exome Sequencing Proj ect (http://evs.gs.washington.edu/EVS/; dbSNP rs114674819). -

MYO1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.96	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.17
Sift	Benign	0.061	T;T
Sift4G	Uncertain	0.040	D;D
Polyphen		0.0070	B;B
Vest4		0.080
MVP		0.44
MPC		0.12
ClinPred		0.016	T
GERP RS		-4.9
Varity_R		0.12
gMVP		0.18

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: rs114674819; hg19: chr12-57437975;