chr17-18118598-C-T

Variant names:

• chr17-18118598-C-T
• rs55821557
• NM_016239.4:c.-203C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016239.4(MYO15A):​c.-203C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 700,294 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO15A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (2 hom.)
• Consequence: MYO15A NM_016239.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.64
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for MYO15A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-18118598-C-T is Benign according to our data. Variant chr17-18118598-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 322103.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00392 (597/152360) while in subpopulation AFR AF = 0.013 (542/41574). AF 95% confidence interval is 0.0121. There are 3 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.-203C>T		5_prime_UTR	Exon 2 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.-203C>T		5_prime_UTR	Exon 2 of 66	ENSP00000495481.1	Q9UKN7-1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 596 AN: 152242 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000637 AC: 349 AN: 547934 Hom.: 2 Cov.: 7 AF XY: 0.000563 AC XY: 161 AN XY: 286128

African (AFR) AF: 0.0141 AC: 200 AN: 14228

American (AMR) AF: 0.00154 AC: 30 AN: 19500

Ashkenazi Jewish (ASJ) AF: 0.000970 AC: 14 AN: 14426

East Asian (EAS) AF: 0.0000634 AC: 2 AN: 31538

South Asian (SAS) AF: 0.00 AC: 0 AN: 48138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30422

Middle Eastern (MID) AF: 0.00138 AC: 3 AN: 2170

European-Non Finnish (NFE) AF: 0.000153 AC: 55 AN: 358310

Other (OTH) AF: 0.00154 AC: 45 AN: 29202

GnomAD4 genome AF: 0.00392 AC: 597 AN: 152360 Hom.: 3 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74508

African (AFR) AF: 0.0130 AC: 542 AN: 41574

American (AMR) AF: 0.00235 AC: 36 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00279 Hom.: 1

Bravo AF: 0.00467

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	10
DANN	Benign	0.87
PhyloP100		-1.6
Mutation Taster		=299/1	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: rs55821557; hg19: chr17-18021912;