rs3758449

Variant names:

• chr10-26157383-G-A
• rs3758449
• NM_017433.5:c.2867G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017433.5(MYO3A):​c.2867G>A​(p.Ser956Asn) variant causes a missense change. The variant allele was found at a frequency of 0.533 in 1,613,650 control chromosomes in the GnomAD database, including 231,940 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (20443 hom., cov: 32)
  • Exomes 𝑓: 0.54 (211497 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.36
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 30

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal dominant 90

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.164611E-5).
• BP6: Variant 10-26157383-G-A is Benign according to our data. Variant chr10-26157383-G-A is described in ClinVar as Benign. ClinVar VariationId is 45804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	NM_017433.5	MANE Select	c.2867G>A	p.Ser956Asn	missense	Exon 26 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.2867G>A	p.Ser956Asn	missense	Exon 26 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.1777-54460G>A		intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000916509.1		c.2867G>A	p.Ser956Asn	missense	Exon 26 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78050 AN: 151834 Hom.: 20442 Cov.: 32

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.508

GnomAD2 exomes AF: 0.502 AC: 126069 AN: 251282 AF XY: 0.508

Gnomad AFR exome AF: 0.462

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.535 AC: 782019 AN: 1461698 Hom.: 211497 Cov.: 56 AF XY: 0.534 AC XY: 388628 AN XY: 727172

African (AFR) AF: 0.467 AC: 15645 AN: 33476

American (AMR) AF: 0.409 AC: 18285 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 13503 AN: 26128

East Asian (EAS) AF: 0.339 AC: 13460 AN: 39684

South Asian (SAS) AF: 0.487 AC: 41972 AN: 86258

European-Finnish (FIN) AF: 0.581 AC: 31055 AN: 53416

Middle Eastern (MID) AF: 0.558 AC: 3221 AN: 5768

European-Non Finnish (NFE) AF: 0.551 AC: 613148 AN: 1111854

Other (OTH) AF: 0.525 AC: 31730 AN: 60390

GnomAD4 genome AF: 0.514 AC: 78075 AN: 151952 Hom.: 20443 Cov.: 32 AF XY: 0.514 AC XY: 38203 AN XY: 74278

African (AFR) AF: 0.465 AC: 19242 AN: 41420

American (AMR) AF: 0.480 AC: 7331 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1832 AN: 3472

East Asian (EAS) AF: 0.332 AC: 1717 AN: 5170

South Asian (SAS) AF: 0.499 AC: 2402 AN: 4816

European-Finnish (FIN) AF: 0.589 AC: 6205 AN: 10538

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37712 AN: 67966

Other (OTH) AF: 0.508 AC: 1069 AN: 2104

Alfa AF: 0.538 Hom.: 110830

Bravo AF: 0.499

TwinsUK AF: 0.543 AC: 2015

ALSPAC AF: 0.544 AC: 2097

ESP6500AA AF: 0.466 AC: 2054

ESP6500EA AF: 0.549 AC: 4723

ExAC AF: 0.506 AC: 61470

Asia WGS AF: 0.424 AC: 1474 AN: 3478

EpiCase AF: 0.555

EpiControl AF: 0.560

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Autosomal recessive nonsyndromic hearing loss 30 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.26
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.000072	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.48	N
PhyloP100		5.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.14
Sift	Benign	0.75	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.058
ClinPred		0.0026	T
GERP RS		4.2
Varity_R		0.10
gMVP		0.19
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3758449; hg19: chr10-26446312; COSMIC: COSV56323742;