chr10-25934301-A-G

Variant names:

• chr10-25934301-A-G
• rs7073224
• NM_017433.5:c.-132A>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.-132A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0797 in 152,362 control chromosomes in the GnomAD database, including 597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (597 hom., cov: 32)
  • Exomes 𝑓: 0.11 (0 hom.)
• Consequence: MYO3A NM_017433.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.398
• Publications: 4 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):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 30

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal dominant 90

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000226304 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 10-25934301-A-G is Benign according to our data. Variant chr10-25934301-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 299639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 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.-132A>G		5_prime_UTR	Exon 1 of 35	NP_059129.3
	MYO3A	NM_001368265.1		c.-132A>G		5_prime_UTR	Exon 1 of 8	NP_001355194.1	Q8NEV4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.-132A>G		5_prime_UTR	Exon 1 of 35	ENSP00000495965.1	Q8NEV4-1
	MYO3A	ENST00000376302.5	TSL:1	c.-132A>G		5_prime_UTR	Exon 1 of 8	ENSP00000365479.1	Q8NEV4-2
	MYO3A	ENST00000916509.1		c.-132A>G		5_prime_UTR	Exon 1 of 33	ENSP00000586568.1

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12095 AN: 152062 Hom.: 593 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0904

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0621

GnomAD4 exome AF: 0.106 AC: 20 AN: 188 Hom.: 0 Cov.: 0 AF XY: 0.106 AC XY: 18 AN XY: 170

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 6

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.110 AC: 18 AN: 164

Other (OTH) AF: 0.250 AC: 2 AN: 8

GnomAD4 genome AF: 0.0797 AC: 12125 AN: 152174 Hom.: 597 Cov.: 32 AF XY: 0.0793 AC XY: 5900 AN XY: 74412

African (AFR) AF: 0.138 AC: 5737 AN: 41528

American (AMR) AF: 0.0466 AC: 714 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4826

European-Finnish (FIN) AF: 0.0904 AC: 959 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0638 AC: 4338 AN: 67968

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0668 Hom.: 134

Bravo AF: 0.0788

Asia WGS AF: 0.00895 AC: 32 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive nonsyndromic hearing loss 30 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	7.7
DANN	Benign	0.30
PhyloP100		-0.40
PromoterAI		0.051	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs7073224; hg19: chr10-26223230;