NM_016239.4:c.4038+6_4038+7delCA

Variant names:

• chr17-18130815-TCA-T
• rs1491110483
• NM_016239.4:c.4038+6_4038+7delCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_016239.4(MYO15A):​c.4038+6_4038+7delCA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,600,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. 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 0.00010 (0 hom., cov: 12)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MYO15A NM_016239.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.468
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 17-18130815-TCA-T is Benign according to our data. Variant chr17-18130815-TCA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504980.

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.4038+6_4038+7delCA		splice_region 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.4038+6_4038+7delCA		splice_region intron	N/A	ENSP00000495481.1	Q9UKN7-1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 15 AN: 142986 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.000395

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000489 AC: 12 AN: 245354 AF XY: 0.0000450

Gnomad AFR exome AF: 0.000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1457718 Hom.: 0 AF XY: 0.00000965 AC XY: 7 AN XY: 725428

African (AFR) AF: 0.000329 AC: 11 AN: 33392

American (AMR) AF: 0.0000224 AC: 1 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52454

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5464

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109624

Other (OTH) AF: 0.0000166 AC: 1 AN: 60214

GnomAD4 genome AF: 0.000105 AC: 15 AN: 143098 Hom.: 0 Cov.: 12 AF XY: 0.0000868 AC XY: 6 AN XY: 69138

African (AFR) AF: 0.000393 AC: 15 AN: 38126

American (AMR) AF: 0.00 AC: 0 AN: 13710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 4808

South Asian (SAS) AF: 0.00 AC: 0 AN: 4332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66068

Other (OTH) AF: 0.00 AC: 0 AN: 1950

Alfa AF: 0.000337 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1491110483; hg19: chr17-18034129;