rs150128469

Variant names:

• chr17-18138951-A-G
• rs150128469
• NM_016239.4:c.5133+15A>G

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.5133+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,610,008 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (16 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.440
• Publications: 1 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-18138951-A-G is Benign according to our data. Variant chr17-18138951-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178442.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00213 (324/152330) while in subpopulation NFE AF = 0.00276 (188/68032). AF 95% confidence interval is 0.00244. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 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.5133+15A>G		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.5133+15A>G		intron	N/A	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000646238.1		n.397+15A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00265 AC: 637 AN: 240162 AF XY: 0.00272

Gnomad AFR exome AF: 0.000758

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00307

GnomAD4 exome AF: 0.00299 AC: 4359 AN: 1457678 Hom.: 16 Cov.: 30 AF XY: 0.00303 AC XY: 2198 AN XY: 724712

African (AFR) AF: 0.000658 AC: 22 AN: 33442

American (AMR) AF: 0.00195 AC: 86 AN: 44148

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 497 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.000947 AC: 81 AN: 85506

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52928

Middle Eastern (MID) AF: 0.00540 AC: 31 AN: 5746

European-Non Finnish (NFE) AF: 0.00306 AC: 3396 AN: 1109974

Other (OTH) AF: 0.00405 AC: 244 AN: 60258

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74488

African (AFR) AF: 0.000770 AC: 32 AN: 41572

American (AMR) AF: 0.000980 AC: 15 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

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: 0.00276 AC: 188 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00506 Hom.: 1

Bravo AF: 0.00238

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.017
DANN	Benign	0.29
PhyloP100		-0.44
Mutation Taster		=100/0	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: rs150128469; hg19: chr17-18042265;