rs201230033

Variant names:

• chr17-18161366-C-A
• rs201230033
• NM_016239.4:c.9436C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-18161366-C-A
• chr17-18161366-C-T

Variant summary

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

The NM_016239.4(MYO15A):​c.9436C>A​(p.His3146Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H3146Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.922
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.9436C>A	p.His3146Asn	missense_variant	Exon 57 of 66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.9439C>A	p.His3147Asn	missense_variant	Exon 55 of 64		XP_016880204.1
MYO15A	XM_017024714.3	c.9376C>A	p.His3126Asn	missense_variant	Exon 54 of 63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.9436C>A	p.His3146Asn	missense_variant	Exon 57 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461822 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 0.0000504 AC: 2 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;D;D;.;.;.;.;.
Eigen	Benign	0.070
Eigen_PC	Benign	0.039
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.79	T;.;T;T;T;D;D;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.4	.;M;M;.;.;.;.;.
PhyloP100		0.92
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-4.2	.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.011	.;D;.;.;.;D;.;.
Sift4G	Uncertain	0.0050	D;D;.;D;.;D;D;D
Polyphen		0.49	.;P;P;.;.;.;.;.
Vest4		0.63
MutPred		0.71		Loss of disorder (P = 0.2731);Loss of disorder (P = 0.2731);Loss of disorder (P = 0.2731);.;.;.;.;.;
MVP		0.86
ClinPred		0.82	D
GERP RS		0.054
Varity_R		0.32
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201230033; hg19: chr17-18064680;