17-18143589-G-T

Variant names:

• chr17-18143589-G-T
• rs542354280
• NM_016239.4:c.5934G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016239.4(MYO15A):​c.5934G>T​(p.Gln1978His) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,411,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q1978Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.36
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39307752).

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.5934G>T	p.Gln1978His	missense	Exon 26 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.5934G>T	p.Gln1978His	missense	Exon 26 of 66	ENSP00000495481.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411762 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 697596

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32370

American (AMR) AF: 0.00 AC: 0 AN: 37262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25298

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37028

South Asian (SAS) AF: 0.00 AC: 0 AN: 80284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5210

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085758

Other (OTH) AF: 0.00 AC: 0 AN: 58470

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.65
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.37	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.33
Sift	Benign	0.15	T
Sift4G	Benign	0.11	T
Polyphen		0.41	B
Vest4		0.21
MutPred		0.43		Gain of methylation at R1976 (P = 0.0495)
MVP		0.70
ClinPred		0.28	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs542354280; hg19: chr17-18046903;