rs62073604

Variant names:

• chr17-18162574-T-C
• rs62073604
• NM_016239.4:c.9518-11T>C

Variant summary

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

The NM_016239.4(MYO15A):​c.9518-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,612,884 control chromosomes in the GnomAD database, including 29,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2871 hom., cov: 33)
  • Exomes 𝑓: 0.18 (26151 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Scores: Splicing: ADA: 0.0001856
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.137
• Publications: 6 publications found

Genes affected

MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]

MYO15A Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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=-0.81).
• BP6: Variant 17-18162574-T-C is Benign according to our data. Variant chr17-18162574-T-C is described in ClinVar as Benign. ClinVar VariationId is 45775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. 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
	MYO15A	NM_016239.4	MANE Select	c.9518-11T>C		intron	N/A	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.9518-11T>C		intron	N/A	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000433411.7	TSL:1	n.968-11T>C		intron	N/A
	MYO15A	ENST00000473013.1	TSL:1	n.702-11T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28767 AN: 152100 Hom.: 2857 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.00828

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.169 AC: 41433 AN: 245520 AF XY: 0.174

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.00452

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.184 AC: 269281 AN: 1460664 Hom.: 26151 Cov.: 33 AF XY: 0.186 AC XY: 134874 AN XY: 726592

African (AFR) AF: 0.221 AC: 7380 AN: 33464

American (AMR) AF: 0.113 AC: 5054 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 6347 AN: 26118

East Asian (EAS) AF: 0.00280 AC: 111 AN: 39690

South Asian (SAS) AF: 0.186 AC: 16075 AN: 86202

European-Finnish (FIN) AF: 0.143 AC: 7570 AN: 53028

Middle Eastern (MID) AF: 0.305 AC: 1759 AN: 5762

European-Non Finnish (NFE) AF: 0.192 AC: 213608 AN: 1111404

Other (OTH) AF: 0.189 AC: 11377 AN: 60338

GnomAD4 genome AF: 0.189 AC: 28830 AN: 152220 Hom.: 2871 Cov.: 33 AF XY: 0.184 AC XY: 13705 AN XY: 74434

African (AFR) AF: 0.212 AC: 8781 AN: 41510

American (AMR) AF: 0.164 AC: 2508 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 841 AN: 3472

East Asian (EAS) AF: 0.00830 AC: 43 AN: 5182

South Asian (SAS) AF: 0.172 AC: 832 AN: 4828

European-Finnish (FIN) AF: 0.146 AC: 1553 AN: 10614

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13613 AN: 67990

Other (OTH) AF: 0.212 AC: 449 AN: 2114

Alfa AF: 0.198 Hom.: 579

Bravo AF: 0.193

Asia WGS AF: 0.108 AC: 374 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.61
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.10		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: rs62073604; hg19: chr17-18065888;