rs75801377

chr10-26173853-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017433.5(MYO3A):c.3589G>A(p.Glu1197Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000753 in 1,614,012 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (7 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.48

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=0.0036109388).
• BP6: Variant 10-26173853-G-A is Benign according to our data. Variant chr10-26173853-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 164628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-26173853-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00398 (606/152300) while in subpopulation AFR AF= 0.0139 (578/41554). AF 95% confidence interval is 0.013. There are 5 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO3A	NM_017433.5	c.3589G>A	p.Glu1197Lys	missense_variant	30/35	ENST00000642920.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO3A	ENST00000642920.2	c.3589G>A	p.Glu1197Lys	missense_variant	30/35		NM_017433.5	P1
MYO3A	ENST00000543632.5	c.1777-37990G>A		intron_variant		1
MYO3A	ENST00000647478.1	c.*1393+3314G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 597 AN: 152182 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000441

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00107 AC: 268 AN: 250560 Hom.: 2 AF XY: 0.000723 AC XY: 98 AN XY: 135592

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000417 AC: 609 AN: 1461712 Hom.: 7 Cov.: 32 AF XY: 0.000329 AC XY: 239 AN XY: 727150

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00398 AC: 606 AN: 152300 Hom.: 5 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74466

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000603 Hom.: 1

Bravo AF: 0.00446

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00131 AC: 159

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Glu1197Lys in Exon 30 of MYO3A: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (41/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs75801377). -

Autosomal recessive nonsyndromic hearing loss 30 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	4.7
Dann	Benign	0.33
DEOGEN2	Benign	0.046	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
Polyphen		0.0030	B;B
Vest4		0.19
MVP		0.71
MPC		0.068
ClinPred		0.00096	T
GERP RS		2.5
Varity_R		0.045
gMVP		0.14

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: rs75801377; hg19: chr10-26462782; COSMIC: COSV56326333;