rs3740231

Variant names:

• chr10-26174114-A-T
• rs3740231
• NM_017433.5:c.3850A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-26174114-A-T
• chr10-26174114-A-C
• chr10-26174114-A-G

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.3850A>T​(p.Thr1284Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 1,613,914 control chromosomes in the GnomAD database, including 146,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12536 hom., cov: 32)
  • Exomes 𝑓: 0.43 (134459 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0610
• Publications: 34 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=1.809597E-4).
• BP6: Variant 10-26174114-A-T is Benign according to our data. Variant chr10-26174114-A-T is described in ClinVar as Benign. ClinVar VariationId is 45809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.449 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.3850A>T	p.Thr1284Ser	missense	Exon 30 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.3850A>T	p.Thr1284Ser	missense	Exon 30 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000543632.5	TSL:1	c.1777-37729A>T		intron	N/A	ENSP00000445909.1	F5H0U9
	MYO3A	ENST00000916509.1		c.3850A>T	p.Thr1284Ser	missense	Exon 30 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60957 AN: 151974 Hom.: 12535 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.412

GnomAD2 exomes AF: 0.412 AC: 103340 AN: 250968 AF XY: 0.419

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.447

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.433

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.428 AC: 624988 AN: 1461822 Hom.: 134459 Cov.: 66 AF XY: 0.429 AC XY: 311934 AN XY: 727206

African (AFR) AF: 0.338 AC: 11322 AN: 33474

American (AMR) AF: 0.356 AC: 15942 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 11498 AN: 26134

East Asian (EAS) AF: 0.345 AC: 13676 AN: 39698

South Asian (SAS) AF: 0.451 AC: 38868 AN: 86252

European-Finnish (FIN) AF: 0.461 AC: 24633 AN: 53402

Middle Eastern (MID) AF: 0.486 AC: 2803 AN: 5768

European-Non Finnish (NFE) AF: 0.432 AC: 480563 AN: 1111980

Other (OTH) AF: 0.425 AC: 25683 AN: 60394

GnomAD4 genome AF: 0.401 AC: 60969 AN: 152092 Hom.: 12536 Cov.: 32 AF XY: 0.403 AC XY: 29941 AN XY: 74326

African (AFR) AF: 0.332 AC: 13761 AN: 41482

American (AMR) AF: 0.395 AC: 6041 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1553 AN: 3468

East Asian (EAS) AF: 0.333 AC: 1724 AN: 5182

South Asian (SAS) AF: 0.465 AC: 2243 AN: 4820

European-Finnish (FIN) AF: 0.459 AC: 4846 AN: 10552

Middle Eastern (MID) AF: 0.503 AC: 147 AN: 292

European-Non Finnish (NFE) AF: 0.435 AC: 29547 AN: 67970

Other (OTH) AF: 0.412 AC: 872 AN: 2114

Alfa AF: 0.431 Hom.: 10639

Bravo AF: 0.387

TwinsUK AF: 0.422 AC: 1566

ALSPAC AF: 0.428 AC: 1648

ESP6500AA AF: 0.329 AC: 1450

ESP6500EA AF: 0.430 AC: 3694

ExAC AF: 0.414 AC: 50240

Asia WGS AF: 0.403 AC: 1400 AN: 3478

EpiCase AF: 0.444

EpiControl AF: 0.446

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.048
DANN	Benign	0.54
DEOGEN2	Benign	0.055	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.061
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.14
Sift	Benign	0.39	T
Sift4G	Benign	0.78	T
Polyphen		0.0030	B
Vest4		0.0090
MutPred		0.054		Gain of phosphorylation at S1280 (P = 0.1471)
MPC		0.057
ClinPred		0.0075	T
GERP RS		-3.4
Varity_R		0.036
gMVP		0.066
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3740231; hg19: chr10-26463043; COSMIC: COSV56323753;