rs16926628

Positions:

chr10-26168708-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_017433.5(MYO3A):c.3112-4T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,610,790 control chromosomes in the GnomAD database, including 10,752 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1317 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9435 hom. )

Consequence

MYO3A
NM_017433.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001928

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.378

Variant links:

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]

MYO3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 10-26168708-T-C is Benign according to our data. Variant chr10-26168708-T-C is described in ClinVar as [Benign]. Clinvar id is 45807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5 linkuse as main transcript	c.3112-4T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2 linkuse as main transcript	c.3112-4T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NM_017433.5	P1	Q8NEV4-1
MYO3A	ENST00000543632.5 linkuse as main transcript	c.1777-43135T>C	intron_variant	1
MYO3A	ENST00000647478.1 linkuse as main transcript	c.*1107-4T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant
MYO3A	ENST00000477691.2 linkuse as main transcript	n.338-4T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18787

AN:

152100

Hom.:

1316

Cov.:

show subpopulations

Gnomad AFR

AF:

0.172

Gnomad AMI

AF:

0.175

Gnomad AMR

AF:

0.0876

Gnomad ASJ

AF:

0.0778

Gnomad EAS

AF:

0.00192

Gnomad SAS

AF:

0.0345

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.106

GnomAD3 exomes

AF:

0.0925

AC:

23169

AN:

250372

Hom.:

1371

AF XY:

0.0912

AC XY:

12340

AN XY:

135358

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.0511

Gnomad ASJ exome

AF:

0.0742

Gnomad EAS exome

AF:

0.00234

Gnomad SAS exome

AF:

0.0372

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.0832

GnomAD4 exome

AF:

0.108

AC:

157964

AN:

1458572

Hom.:

9435

Cov.:

AF XY:

0.106

AC XY:

77034

AN XY:

725760

show subpopulations

Gnomad4 AFR exome

AF:

0.172

Gnomad4 AMR exome

AF:

0.0536

Gnomad4 ASJ exome

AF:

0.0755

Gnomad4 EAS exome

AF:

0.00136

Gnomad4 SAS exome

AF:

0.0370

Gnomad4 FIN exome

AF:

0.123

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.102

GnomAD4 genome

AF:

0.124

AC:

18799

AN:

152218

Hom.:

1317

Cov.:

AF XY:

0.122

AC XY:

9044

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.172

Gnomad4 AMR

AF:

0.0874

Gnomad4 ASJ

AF:

0.0778

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.0344

Gnomad4 FIN

AF:

0.128

Gnomad4 NFE

AF:

0.119

Gnomad4 OTH

AF:

0.105

Alfa

AF:

0.113

Hom.:

1630

Bravo

AF:

0.125

Asia WGS

AF:

0.0270

AC:

AN:

3476

EpiCase

AF:

0.110

EpiControl

AF:

0.114

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	3112-4T>C in Intron 27 of MYO3A: This variant is not expected to have clinical s ignificance because it is not located within the conserved splice consensus sequ ence and has been identified in 17.3% (647/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs16926628). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 30

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 27, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over