rs61731652

chr10-26026528-G-Cchr10-26026528-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017433.5(MYO3A):c.949G>C(p.Ala317Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000536 in 1,614,022 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 3.02

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008818686).
• BP6: Variant 10-26026528-G-C is Benign according to our data. Variant chr10-26026528-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178622.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00296 (451/152286) while in subpopulation AFR AF= 0.0105 (437/41558). AF 95% confidence interval is 0.0097. There are 3 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.949G>C	p.Ala317Pro	missense_variant	10/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.949G>C	p.Ala317Pro	missense_variant	10/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.949G>C	p.Ala317Pro	missense_variant	9/17	1
MYO3A	ENST00000642197.1	n.1153G>C		non_coding_transcript_exon_variant	10/27
MYO3A	ENST00000647478.1	c.949G>C	p.Ala317Pro	missense_variant, NMD_transcript_variant	9/30

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152168 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000716 AC: 180 AN: 251258 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135806

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 414 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 168 AN XY: 727176

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.000358

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: 0.00000540

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152286 Hom.: 3 Cov.: 33 AF XY: 0.00287 AC XY: 214 AN XY: 74470

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000168 Hom.: 1

Bravo AF: 0.00327

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 30 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 17, 2020	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.949G>C (p.A317P) alteration is located in exon 10 (coding exon 8) of the MYO3A gene. This alteration results from a G to C substitution at nucleotide position 949, causing the alanine (A) at amino acid position 317 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 15, 2017

p.Ala317Pro in exon 10 of MYO3A: This variant is not expected to have clinical s ignificance because it has been identified in 1.1% (112/10288) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61731652). -

MYO3A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as 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	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.087	T;T;T
Eigen	Benign	0.089
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0088	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.37	T
Polyphen		0.0040	B;B;B
Vest4		0.22, 0.26
MVP		0.82
MPC		0.078
ClinPred		0.0060	T
GERP RS		4.8
Varity_R		0.18
gMVP		0.60

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: rs61731652; hg19: chr10-26315457;