rs121908966

Positions:

• chr17-18145929-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_016239.4(MYO15A):​c.6331A>T​(p.Asn2111Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.02

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain MyTH4 1 (size 152) in uniprot entity MYO15_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_016239.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 17-18145929-A-T is Pathogenic according to our data. Variant chr17-18145929-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 6951.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.6331A>T	p.Asn2111Tyr	missense_variant	30/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.6331A>T	p.Asn2111Tyr	missense_variant	30/66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Wonkam Laboratory, Johns Hopkins University	Jan 06, 2024	The variant NM_016239.3 c.6331A>T is located in a mutational hot spot and/or critical and well-established functional domain of MYO15A (PM1), Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3), Patient's phenotype or family history is highly specific for a disease with a single genetic etiology ( PP4), Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation (PP5) -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 29, 1998	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.2	.;M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.3	.;D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.57
MutPred		0.88		Gain of methylation at K2116 (P = 0.045);Gain of methylation at K2116 (P = 0.045);Gain of methylation at K2116 (P = 0.045);
MVP		0.91
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908966; hg19: chr17-18049243;