chr17-18142183-T-G

Position:

• chr17-18142183-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_016239.4(MYO15A):​c.5754T>G​(p.Ile1918Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,798 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 1.01

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011315256).
• BP6: Variant 17-18142183-T-G is Benign according to our data. Variant chr17-18142183-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178444.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.5754T>G	p.Ile1918Met	missense_variant	24/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.5754T>G	p.Ile1918Met	missense_variant	24/66		NM_016239.4	ENSP00000495481	P1
MYO15A	ENST00000412324.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 293 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00192 AC: 478 AN: 249312 Hom.: 0 AF XY: 0.00190 AC XY: 257 AN XY: 135308

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000981

Gnomad FIN exome AF: 0.00334

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.00221 AC: 3236 AN: 1461462 Hom.: 12 Cov.: 33 AF XY: 0.00229 AC XY: 1663 AN XY: 727026

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.00315

Gnomad4 NFE exome AF: 0.00250

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74500

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00271 Hom.: 1

Bravo AF: 0.00180

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000458 AC: 2

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00195 AC: 237

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2019

- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2017

p.Ile1918Met in exon 24 of MYO15A: This variant is not expected to have clinica l significance because it has been identified in 0.3% (394/126610) of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs150403702). ACMG/AMP criteria applied: BS1. -

MYO15A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2022

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.019	T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.68	T;.;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Benign	0.97	.;L;L
MutationTaster	Benign	0.80	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	.;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.057	.;T;.
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		0.88	.;P;P
Vest4		0.54
MVP		0.77
ClinPred		0.031	T
GERP RS		1.3
Varity_R		0.088
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs150403702; hg19: chr17-18045497;