rs854778

Variant names:

• chr17-18142744-A-C
• rs854778
• NM_016239.4:c.5826-12A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-18142744-A-C
• chr17-18142744-A-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.5826-12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 1,610,714 control chromosomes in the GnomAD database, including 436,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene MYO15A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.75 (43442 hom., cov: 30)
  • Exomes 𝑓: 0.73 (393105 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Scores: Splicing: ADA: 0.00001800
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.446
• 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

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=-0.9).
• BP6: Variant 17-18142744-A-C is Benign according to our data. Variant chr17-18142744-A-C is described in ClinVar as Benign. ClinVar VariationId is 45751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.796 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.5826-12A>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.5826-12A>C		intron	N/A	ENSP00000495481.1	Q9UKN7-1

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114275 AN: 151696 Hom.: 43374 Cov.: 30

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.800

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.758

GnomAD2 exomes AF: 0.717 AC: 175518 AN: 244836 AF XY: 0.707

Gnomad AFR exome AF: 0.796

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.806

Gnomad EAS exome AF: 0.600

Gnomad FIN exome AF: 0.753

Gnomad NFE exome AF: 0.737

Gnomad OTH exome AF: 0.736

GnomAD4 exome AF: 0.732 AC: 1067674 AN: 1458900 Hom.: 393105 Cov.: 38 AF XY: 0.726 AC XY: 527027 AN XY: 725620

African (AFR) AF: 0.809 AC: 27055 AN: 33446

American (AMR) AF: 0.767 AC: 34149 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 21023 AN: 26040

East Asian (EAS) AF: 0.598 AC: 23695 AN: 39632

South Asian (SAS) AF: 0.568 AC: 48858 AN: 85970

European-Finnish (FIN) AF: 0.757 AC: 40123 AN: 53010

Middle Eastern (MID) AF: 0.746 AC: 4295 AN: 5754

European-Non Finnish (NFE) AF: 0.742 AC: 824062 AN: 1110230

Other (OTH) AF: 0.737 AC: 44414 AN: 60286

GnomAD4 genome AF: 0.754 AC: 114403 AN: 151814 Hom.: 43442 Cov.: 30 AF XY: 0.748 AC XY: 55535 AN XY: 74212

African (AFR) AF: 0.803 AC: 33200 AN: 41344

American (AMR) AF: 0.762 AC: 11647 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 2777 AN: 3472

East Asian (EAS) AF: 0.601 AC: 3079 AN: 5124

South Asian (SAS) AF: 0.562 AC: 2693 AN: 4794

European-Finnish (FIN) AF: 0.752 AC: 7940 AN: 10554

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.745 AC: 50641 AN: 67930

Other (OTH) AF: 0.759 AC: 1603 AN: 2112

Alfa AF: 0.764 Hom.: 8413

Bravo AF: 0.758

Asia WGS AF: 0.592 AC: 2060 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Autosomal recessive nonsyndromic hearing loss 3 (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.9
DANN	Benign	0.39
PhyloP100		0.45
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
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: rs854778; hg19: chr17-18046058; COSMIC: COSV52753857; COSMIC: COSV52753857;