17-18121262-A-G

Variant names:

• chr17-18121262-A-G
• rs372125621
• NM_016239.4:c.2462A>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.2462A>G​(p.Gln821Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000769 in 1,300,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q821P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08747789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.2462A>G	p.Gln821Arg	missense_variant	Exon 2 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.2462A>G	p.Gln821Arg	missense_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000583079.1	n.2095A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.69e-7 AC: 1 AN: 1300590 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 641540

⚠️ 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: 25588

American (AMR) AF: 0.00 AC: 0 AN: 25832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21602

East Asian (EAS) AF: 0.00 AC: 0 AN: 26928

South Asian (SAS) AF: 0.00 AC: 0 AN: 72132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3844

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038698

Other (OTH) AF: 0.0000188 AC: 1 AN: 53182

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.8
DANN	Benign	0.43
DEOGEN2	Benign	0.0025	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.31	T;.;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-2.0	.;N;N
PhyloP100		-0.076
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.010	.;N;.
REVEL	Benign	0.20
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	.;B;B
Vest4		0.068
MutPred		0.25		Gain of MoRF binding (P = 0.0287);Gain of MoRF binding (P = 0.0287);Gain of MoRF binding (P = 0.0287);
MVP		0.42
ClinPred		0.035	T
GERP RS		2.0
Varity_R		0.022
gMVP		0.15

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: rs372125621; hg19: chr17-18024576;