rs16960959

chr17-18150908-G-Achr17-18150908-G-Cchr17-18150908-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016239.4(MYO15A):c.7468G>A(p.Ala2490Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00665 in 1,601,094 control chromosomes in the GnomAD database, including 605 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (354 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (251 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.471

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001448214).
• BP6: Variant 17-18150908-G-A is Benign according to our data. Variant chr17-18150908-G-A is described in ClinVar as [Benign]. Clinvar id is 45759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18150908-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.7468G>A	p.Ala2490Thr	missense_variant	38/66	ENST00000647165.2
LOC124903944	XR_007065652.1	n.377+695C>T		intron_variant, non_coding_transcript_variant
MYO15A	XM_017024715.3	c.7471G>A	p.Ala2491Thr	missense_variant	36/64
MYO15A	XM_017024714.3	c.7408G>A	p.Ala2470Thr	missense_variant	35/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.7468G>A	p.Ala2490Thr	missense_variant	38/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5466 AN: 152120 Hom.: 354 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.00907 AC: 2040 AN: 224928 Hom.: 96 AF XY: 0.00697 AC XY: 851 AN XY: 122076

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.00759

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000619

Gnomad SAS exome AF: 0.000208

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.00451

GnomAD4 exome AF: 0.00356 AC: 5163 AN: 1448856 Hom.: 251 Cov.: 33 AF XY: 0.00309 AC XY: 2223 AN XY: 719742

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.00847

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.00746

GnomAD4 genome AF: 0.0360 AC: 5478 AN: 152238 Hom.: 354 Cov.: 32 AF XY: 0.0342 AC XY: 2548 AN XY: 74430

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00416 Hom.: 57

Bravo AF: 0.0402

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.112 AC: 453

ESP6500EA AF: 0.00120 AC: 10

ExAC AF: 0.0106 AC: 1275

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala2490Thr in Exon 38 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 11.0% (370/3368) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs16960959). -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	11
Dann	Benign	0.92
DEOGEN2	Benign	0.0072	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.44	T;.;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.53	T;T;.
Polyphen		0.0	.;B;B
Vest4		0.024
ClinPred		0.00073	T
GERP RS		-0.71
Varity_R		0.037
gMVP		0.20

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: rs16960959; hg19: chr17-18054222;