rs727503318

Variant names:

• chr17-18155377-A-G
• rs727503318
• NM_016239.4:c.8404A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016239.4(MYO15A):​c.8404A>G​(p.Met2802Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.409
• 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), PanelApp Australia
• 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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06844258).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.8404A>G	p.Met2802Val	missense	Exon 47 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.8404A>G	p.Met2802Val	missense	Exon 47 of 66	ENSP00000495481.1
	MYO15A	ENST00000418233.7	TSL:2	c.196A>G	p.Met66Val	missense	Exon 5 of 24	ENSP00000408800.3
	MYO15A	ENST00000644795.1		c.196A>G	p.Met66Val	missense	Exon 5 of 23	ENSP00000495720.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249122 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461444 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727032

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.65	N
PhyloP100		0.41
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Benign	0.40	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.35
MutPred		0.34		Gain of ubiquitination at K2804 (P = 0.0797)
MVP		0.64
ClinPred		0.036	T
GERP RS		0.56
Varity_R		0.041
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs727503318; hg19: chr17-18058691;