rs1999240

chr10-26174201-C-Achr10-26174201-C-T

Variant summary

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

The NM_017433.5(MYO3A):c.3937C>A(p.Arg1313Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,613,926 control chromosomes in the GnomAD database, including 279,409 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26113 hom., cov: 32)
  • Exomes 𝑓: 0.59 (253296 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.64

Genes affected

MYO3A (HGNC:7601): (myosin IIIA) The protein encoded by this gene belongs to the myosin superfamily. Myosins are actin-dependent motor proteins and are categorized into conventional myosins (class II) and unconventional myosins (classes I and III through XV) based on their variable C-terminal cargo-binding domains. Class III myosins, such as this one, have a kinase domain N-terminal to the conserved N-terminal motor domains and are expressed in photoreceptors. The protein encoded by this gene plays an important role in hearing in humans. Three different recessive, loss of function mutations in the encoded protein have been shown to cause nonsyndromic progressive hearing loss. Expression of this gene is highly restricted, with the strongest expression in retina and cochlea. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.7209604E-6).
• BP6: Variant 10-26174201-C-A is Benign according to our data. Variant chr10-26174201-C-A is described in ClinVar as [Benign]. Clinvar id is 45811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26174201-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.3937C>A	p.Arg1313Ser	missense_variant	30/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.3937C>A	p.Arg1313Ser	missense_variant	30/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.1777-37642C>A		intron_variant		1
MYO3A	ENST00000647478.1	c.*1393+3662C>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88781 AN: 151940 Hom.: 26095 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.655

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.598

GnomAD3 exomes AF: 0.601 AC: 151112 AN: 251360 Hom.: 45639 AF XY: 0.600 AC XY: 81525 AN XY: 135854

Gnomad AFR exome AF: 0.544

Gnomad AMR exome AF: 0.649

Gnomad ASJ exome AF: 0.589

Gnomad EAS exome AF: 0.628

Gnomad SAS exome AF: 0.598

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.581

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.588 AC: 858963 AN: 1461868 Hom.: 253296 Cov.: 70 AF XY: 0.587 AC XY: 427232 AN XY: 727238

Gnomad4 AFR exome AF: 0.552

Gnomad4 AMR exome AF: 0.644

Gnomad4 ASJ exome AF: 0.585

Gnomad4 EAS exome AF: 0.671

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.654

Gnomad4 NFE exome AF: 0.579

Gnomad4 OTH exome AF: 0.584

GnomAD4 genome AF: 0.584 AC: 88857 AN: 152058 Hom.: 26113 Cov.: 32 AF XY: 0.590 AC XY: 43816 AN XY: 74294

Gnomad4 AFR AF: 0.551

Gnomad4 AMR AF: 0.608

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.641

Gnomad4 SAS AF: 0.621

Gnomad4 FIN AF: 0.655

Gnomad4 NFE AF: 0.583

Gnomad4 OTH AF: 0.598

Alfa AF: 0.580 Hom.: 65924

Bravo AF: 0.576

TwinsUK AF: 0.571 AC: 2118

ALSPAC AF: 0.587 AC: 2262

ESP6500AA AF: 0.545 AC: 2403

ESP6500EA AF: 0.572 AC: 4916

ExAC AF: 0.598 AC: 72658

Asia WGS AF: 0.625 AC: 2170 AN: 3478

EpiCase AF: 0.585

EpiControl AF: 0.586

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	May 07, 2012	Arg1313Ser in Exon 30 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 45.8% (1712/3738) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs1999240). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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 recessive nonsyndromic hearing loss 30 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	11
Dann	Benign	0.27
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.0083	N
MetaRNN	Benign	0.0000037	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
Polyphen		0.0	B;B
Vest4		0.010
MPC		0.067
ClinPred		0.0018	T
GERP RS		4.1
Varity_R		0.083
gMVP		0.046

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: rs1999240; hg19: chr10-26463130; COSMIC: COSV56323764;