NM_017433.5:c.3094G>A

Variant names:

• chr10-26166161-G-A
• rs34918608
• NM_017433.5:c.3094G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017433.5(MYO3A):​c.3094G>A​(p.Ala1032Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00895 in 1,613,232 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (83 hom.)
• Consequence: MYO3A NM_017433.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.53
• Publications: 9 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), PanelApp Australia, 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=0.011166692).
• BP6: Variant 10-26166161-G-A is Benign according to our data. Variant chr10-26166161-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00802 (1221/152244) while in subpopulation NFE AF = 0.011 (745/68010). AF 95% confidence interval is 0.0103. There are 11 homozygotes in GnomAd4. There are 638 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,SD,AD gene

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.3094G>A	p.Ala1032Thr	missense	Exon 27 of 35	NP_059129.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.3094G>A	p.Ala1032Thr	missense	Exon 27 of 35	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1777-45682G>A		intron	N/A	ENSP00000445909.1
	MYO3A	ENST00000916509.1		c.3094G>A	p.Ala1032Thr	missense	Exon 27 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1221 AN: 152126 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00815 AC: 2047 AN: 251272 AF XY: 0.00802

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0237

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.00904 AC: 13214 AN: 1460988 Hom.: 83 Cov.: 30 AF XY: 0.00901 AC XY: 6550 AN XY: 726900

African (AFR) AF: 0.00108 AC: 36 AN: 33474

American (AMR) AF: 0.00311 AC: 139 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00589 AC: 154 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00152 AC: 131 AN: 86226

European-Finnish (FIN) AF: 0.0252 AC: 1344 AN: 53420

Middle Eastern (MID) AF: 0.00108 AC: 6 AN: 5530

European-Non Finnish (NFE) AF: 0.00987 AC: 10966 AN: 1111432

Other (OTH) AF: 0.00724 AC: 437 AN: 60358

GnomAD4 genome AF: 0.00802 AC: 1221 AN: 152244 Hom.: 11 Cov.: 33 AF XY: 0.00857 AC XY: 638 AN XY: 74430

African (AFR) AF: 0.00140 AC: 58 AN: 41548

American (AMR) AF: 0.00602 AC: 92 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.0266 AC: 282 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 745 AN: 68010

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00995 Hom.: 37

Bravo AF: 0.00613

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00849 AC: 73

ExAC AF: 0.00847 AC: 1029

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00883

EpiControl AF: 0.00871

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Autosomal recessive nonsyndromic hearing loss 30 (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.081	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.40
Sift	Benign	0.057	T
Sift4G	Benign	0.21	T
Polyphen		0.81	P
Vest4		0.38
MVP		0.86
MPC		0.064
ClinPred		0.045	T
GERP RS		5.2
Varity_R		0.19
gMVP		0.31
Mutation Taster		=93/7	polymorphism

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: rs34918608; hg19: chr10-26455090; COSMIC: COSV56340951;