NM_016239.4:c.-219-14T>C

Variant names:

• chr17-18118568-T-C
• rs854817
• NM_016239.4:c.-219-14T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.-219-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 595,858 control chromosomes in the GnomAD database, including 60,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (18096 hom., cov: 33)
  • Exomes 𝑓: 0.41 (42793 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.962
• Publications: 12 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 17-18118568-T-C is Benign according to our data. Variant chr17-18118568-T-C is described in ClinVar as Benign. ClinVar VariationId is 322102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.687 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.-219-14T>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.-219-14T>C		intron	N/A	ENSP00000495481.1	Q9UKN7-1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70366 AN: 152016 Hom.: 18045 Cov.: 33

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.413 AC: 183388 AN: 443724 Hom.: 42793 Cov.: 5 AF XY: 0.428 AC XY: 99513 AN XY: 232494

African (AFR) AF: 0.667 AC: 8208 AN: 12302

American (AMR) AF: 0.498 AC: 8815 AN: 17710

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 5604 AN: 13230

East Asian (EAS) AF: 0.657 AC: 19251 AN: 29296

South Asian (SAS) AF: 0.703 AC: 31536 AN: 44876

European-Finnish (FIN) AF: 0.382 AC: 10323 AN: 27030

Middle Eastern (MID) AF: 0.470 AC: 891 AN: 1896

European-Non Finnish (NFE) AF: 0.324 AC: 88230 AN: 272116

Other (OTH) AF: 0.417 AC: 10530 AN: 25268

GnomAD4 genome AF: 0.463 AC: 70471 AN: 152134 Hom.: 18096 Cov.: 33 AF XY: 0.473 AC XY: 35186 AN XY: 74374

African (AFR) AF: 0.655 AC: 27202 AN: 41500

American (AMR) AF: 0.486 AC: 7424 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1454 AN: 3470

East Asian (EAS) AF: 0.636 AC: 3279 AN: 5158

South Asian (SAS) AF: 0.707 AC: 3412 AN: 4824

European-Finnish (FIN) AF: 0.415 AC: 4400 AN: 10590

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21883 AN: 67994

Other (OTH) AF: 0.433 AC: 913 AN: 2108

Alfa AF: 0.378 Hom.: 3767

Bravo AF: 0.472

Asia WGS AF: 0.662 AC: 2300 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.82
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs854817; hg19: chr17-18021882; COSMIC: COSV52764452; COSMIC: COSV52764452;