rs372125621

chr17-18121262-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_016239.4(MYO15A):c.2462A>C(p.Gln821Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,451,342 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.020 (76 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (102 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0760

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025024116).
• BP6: Variant 17-18121262-A-C is Benign according to our data. Variant chr17-18121262-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226781.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.2462A>C	p.Gln821Pro	missense_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.2462A>C	p.Gln821Pro	missense_variant	2/66		NM_016239.4	P1
MYO15A	ENST00000583079.1	n.2095A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2947 AN: 150706 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.00197

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.0179

GnomAD3 exomes AF: 0.00544 AC: 386 AN: 70928 Hom.: 2 AF XY: 0.00524 AC XY: 214 AN XY: 40838

Gnomad AFR exome AF: 0.0559

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00455

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00391

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.00426 AC: 5541 AN: 1300528 Hom.: 102 Cov.: 36 AF XY: 0.00416 AC XY: 2669 AN XY: 641502

Gnomad4 AFR exome AF: 0.0741

Gnomad4 AMR exome AF: 0.00589

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00430

Gnomad4 FIN exome AF: 0.000976

Gnomad4 NFE exome AF: 0.00221

Gnomad4 OTH exome AF: 0.00886

GnomAD4 genome AF: 0.0196 AC: 2957 AN: 150814 Hom.: 76 Cov.: 32 AF XY: 0.0191 AC XY: 1410 AN XY: 73706

Gnomad4 AFR AF: 0.0584

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00457

Gnomad4 FIN AF: 0.00197

Gnomad4 NFE AF: 0.00342

Gnomad4 OTH AF: 0.0177

Alfa AF: 0.0142 Hom.: 7

ESP6500AA AF: 0.0351 AC: 70

ESP6500EA AF: 0.00172 AC: 8

ExAC AF: 0.00260 AC: 128

Asia WGS AF: 0.00897 AC: 30 AN: 3358

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

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	Apr 30, 2012	p.Gln821Pro in Exon 02 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 3.7% (56/1508) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1 Benign:1

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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	0.058
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	15
Dann	Benign	0.80
DEOGEN2	Benign	0.019	T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.42	T;.;T
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.85	D
Sift4G	Benign	0.18	T;T;.
Polyphen		0.0	.;B;B
Vest4		0.21
MVP		0.60
ClinPred		0.0081	T
GERP RS		2.0
Varity_R		0.13
gMVP		0.32

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: rs372125621; hg19: chr17-18024576; COSMIC: COSV52754982;