17-18150737-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_016239.4(MYO15A):c.7367C>G(p.Ala2456Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,588,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.19

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]

LOC124903944 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013505936).
• BP6: Variant 17-18150737-C-G is Benign according to our data. Variant chr17-18150737-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164549.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.7367C>G	p.Ala2456Gly	missense_variant	37/66	ENST00000647165.2
LOC124903944	XR_007065652.1	n.377+866G>C		intron_variant, non_coding_transcript_variant
MYO15A	XM_017024715.3	c.7370C>G	p.Ala2457Gly	missense_variant	35/64
MYO15A	XM_017024714.3	c.7307C>G	p.Ala2436Gly	missense_variant	34/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.7367C>G	p.Ala2456Gly	missense_variant	37/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000351 AC: 73 AN: 207972 Hom.: 0 AF XY: 0.000321 AC XY: 36 AN XY: 112322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000664

Gnomad OTH exome AF: 0.000379

GnomAD4 exome AF: 0.000154 AC: 221 AN: 1436092 Hom.: 0 Cov.: 33 AF XY: 0.000163 AC XY: 116 AN XY: 712086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000479

Gnomad4 ASJ exome AF: 0.00637

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000273

Gnomad4 OTH exome AF: 0.000438

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000855 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000224 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 25, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 05, 2015

The p.Ala2456Gly variant in MYO15A has been previously identified by our laborat ory in the heterozygous state in two individuals with hearing loss (LMM unpublis hed data). This variant has been identified in 0.1% (23/24442) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs199953758); however, its frequency is not high enough to rule out a p athogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Ala2456Gly variant is uncertain. -

MYO15A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.037	T;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;.;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.45
MVP		0.89
ClinPred		0.13	T
GERP RS		4.7
Varity_R		0.32
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs199953758; hg19: chr17-18054051; COSMIC: COSV52758080; COSMIC: COSV52758080;