rs9916193

Variant names:

• chr17-18153901-C-G
• rs9916193
• NM_016239.4:c.8088+5C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-18153901-C-G
• chr17-18153901-C-A
• chr17-18153901-C-T

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.8088+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,613,094 control chromosomes in the GnomAD database, including 35,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). The gene MYO15A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.24 (5046 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30421 hom.)
• Consequence: MYO15A NM_016239.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009153
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.49
• Publications: 15 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

LOC105371567 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-18153901-C-G is Benign according to our data. Variant chr17-18153901-C-G is described in ClinVar as Benign. ClinVar VariationId is 226789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.361 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.8088+5C>G		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.8088+5C>G		splice_region intron	N/A	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000418233.7	TSL:2	c.-121+5C>G		splice_region intron	N/A	ENSP00000408800.3	Q9UKN7-2
	MYO15A	ENST00000644795.1		c.-121+5C>G		splice_region intron	N/A	ENSP00000495720.1	A0A2R8Y712

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36360 AN: 151832 Hom.: 5017 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.00851

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.188 AC: 46606 AN: 248254 AF XY: 0.191

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.00457

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.197 AC: 287692 AN: 1461144 Hom.: 30421 Cov.: 54 AF XY: 0.198 AC XY: 143567 AN XY: 726860

African (AFR) AF: 0.373 AC: 12470 AN: 33470

American (AMR) AF: 0.128 AC: 5736 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 7230 AN: 26132

East Asian (EAS) AF: 0.00285 AC: 113 AN: 39700

South Asian (SAS) AF: 0.191 AC: 16434 AN: 86248

European-Finnish (FIN) AF: 0.145 AC: 7668 AN: 52782

Middle Eastern (MID) AF: 0.342 AC: 1971 AN: 5768

European-Non Finnish (NFE) AF: 0.201 AC: 223544 AN: 1111946

Other (OTH) AF: 0.207 AC: 12526 AN: 60378

GnomAD4 genome AF: 0.240 AC: 36446 AN: 151950 Hom.: 5046 Cov.: 32 AF XY: 0.233 AC XY: 17277 AN XY: 74268

African (AFR) AF: 0.366 AC: 15150 AN: 41408

American (AMR) AF: 0.190 AC: 2902 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 966 AN: 3470

East Asian (EAS) AF: 0.00853 AC: 44 AN: 5160

South Asian (SAS) AF: 0.176 AC: 844 AN: 4806

European-Finnish (FIN) AF: 0.149 AC: 1570 AN: 10558

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14205 AN: 67962

Other (OTH) AF: 0.257 AC: 541 AN: 2102

Alfa AF: 0.182 Hom.: 912

Bravo AF: 0.250

Asia WGS AF: 0.120 AC: 418 AN: 3476

EpiCase AF: 0.221

EpiControl AF: 0.229

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Autosomal recessive nonsyndromic hearing loss 3 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.45
PhyloP100		-1.5
PromoterAI		0.0073	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.0020
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: rs9916193; hg19: chr17-18057215;