rs33947968

chr10-26145526-G-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.2497G>T(p.Ala833Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,591,708 control chromosomes in the GnomAD database, including 5,298 homozygotes. In-silico tool predicts 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. A833P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.061 (368 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4930 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 10.0

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=0.010160327).
• BP6: Variant 10-26145526-G-T is Benign according to our data. Variant chr10-26145526-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 45803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26145526-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.2497G>T	p.Ala833Ser	missense_variant	22/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.2497G>T	p.Ala833Ser	missense_variant	22/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.1776+48844G>T		intron_variant		1
MYO3A	ENST00000642197.1	n.2701G>T		non_coding_transcript_exon_variant	22/27
MYO3A	ENST00000647478.1	c.*492G>T		3_prime_UTR_variant, NMD_transcript_variant	20/30

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9295 AN: 152096 Hom.: 368 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0744

Gnomad ASJ AF: 0.0975

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0276

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0885

Gnomad OTH AF: 0.0700

GnomAD3 exomes AF: 0.0637 AC: 15940 AN: 250250 Hom.: 678 AF XY: 0.0646 AC XY: 8745 AN XY: 135286

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.0502

Gnomad ASJ exome AF: 0.0926

Gnomad EAS exome AF: 0.000600

Gnomad SAS exome AF: 0.0298

Gnomad FIN exome AF: 0.0697

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0773

GnomAD4 exome AF: 0.0781 AC: 112399 AN: 1439494 Hom.: 4930 Cov.: 30 AF XY: 0.0770 AC XY: 55262 AN XY: 717456

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0527

Gnomad4 ASJ exome AF: 0.0912

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.0308

Gnomad4 FIN exome AF: 0.0725

Gnomad4 NFE exome AF: 0.0878

Gnomad4 OTH exome AF: 0.0749

GnomAD4 genome AF: 0.0610 AC: 9291 AN: 152214 Hom.: 368 Cov.: 32 AF XY: 0.0597 AC XY: 4444 AN XY: 74414

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.0744

Gnomad4 ASJ AF: 0.0975

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0274

Gnomad4 FIN AF: 0.0689

Gnomad4 NFE AF: 0.0885

Gnomad4 OTH AF: 0.0702

Alfa AF: 0.0808 Hom.: 923

Bravo AF: 0.0606

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0926 AC: 357

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.0933 AC: 802

ExAC AF: 0.0638 AC: 7743

Asia WGS AF: 0.0300 AC: 107 AN: 3478

EpiCase AF: 0.0893

EpiControl AF: 0.0962

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

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	Ala833Ser in Exon 22 of MYO3A: This variant is not expected to have clinical sig nificance because it has been identified in 9.0% (631/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs33947968). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

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	0.21
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
Polyphen		1.0	D;D
Vest4		0.33
MPC		0.37
ClinPred		0.061	T
GERP RS		5.7
Varity_R		0.89
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33947968; hg19: chr10-26434455;