NM_017433.5:c.4438+18T>C

Variant names:

• chr10-26176863-T-C
• rs17739680
• NM_017433.5:c.4438+18T>C

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.4438+18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,611,870 control chromosomes in the GnomAD database, including 9,745 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (784 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8961 hom.)
• Consequence: MYO3A NM_017433.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.204
• Publications: 5 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 (BayesDel_noAF=-0.85).
• BP6: Variant 10-26176863-T-C is Benign according to our data. Variant chr10-26176863-T-C is described in ClinVar as Benign. ClinVar VariationId is 260811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	NM_017433.5	MANE Select	c.4438+18T>C		intron	N/A	NP_059129.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO3A	ENST00000642920.2	MANE Select	c.4438+18T>C		intron	N/A	ENSP00000495965.1
	MYO3A	ENST00000543632.5	TSL:1	c.1777-34980T>C		intron	N/A	ENSP00000445909.1
	MYO3A	ENST00000647478.1		n.*1393+6324T>C		intron	N/A	ENSP00000493932.1

Frequencies

GnomAD3 genomes AF: 0.0966 AC: 14691 AN: 152110 Hom.: 784 Cov.: 32

Gnomad AFR AF: 0.0812

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.0712

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.0339

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0889

GnomAD2 exomes AF: 0.0850 AC: 21336 AN: 250886 AF XY: 0.0854

Gnomad AFR exome AF: 0.0785

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0731

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.105 AC: 153890 AN: 1459642 Hom.: 8961 Cov.: 32 AF XY: 0.104 AC XY: 75281 AN XY: 726314

African (AFR) AF: 0.0790 AC: 2640 AN: 33420

American (AMR) AF: 0.0459 AC: 2054 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0745 AC: 1946 AN: 26120

East Asian (EAS) AF: 0.00136 AC: 54 AN: 39678

South Asian (SAS) AF: 0.0369 AC: 3180 AN: 86210

European-Finnish (FIN) AF: 0.123 AC: 6560 AN: 53382

Middle Eastern (MID) AF: 0.0650 AC: 375 AN: 5768

European-Non Finnish (NFE) AF: 0.118 AC: 131323 AN: 1110014

Other (OTH) AF: 0.0954 AC: 5758 AN: 60326

GnomAD4 genome AF: 0.0965 AC: 14683 AN: 152228 Hom.: 784 Cov.: 32 AF XY: 0.0945 AC XY: 7036 AN XY: 74434

African (AFR) AF: 0.0809 AC: 3359 AN: 41528

American (AMR) AF: 0.0711 AC: 1087 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0776 AC: 269 AN: 3466

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5188

South Asian (SAS) AF: 0.0337 AC: 163 AN: 4830

European-Finnish (FIN) AF: 0.129 AC: 1364 AN: 10600

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8065 AN: 68004

Other (OTH) AF: 0.0880 AC: 186 AN: 2114

Alfa AF: 0.102 Hom.: 163

Bravo AF: 0.0929

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.5
DANN	Benign	0.48
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17739680; hg19: chr10-26465792;