rs2272571

chr17-18143875-G-Achr17-18143875-G-Cchr17-18143875-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.6052G>A(p.Gly2018Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,581,876 control chromosomes in the GnomAD database, including 20,908 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2502 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18406 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.25

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.0833855E-5).
• BP6: Variant 17-18143875-G-A is Benign according to our data. Variant chr17-18143875-G-A is described in ClinVar as [Benign]. Clinvar id is 45754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18143875-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.6052G>A	p.Gly2018Arg	missense_variant	28/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.6052G>A	p.Gly2018Arg	missense_variant	28/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24172 AN: 152100 Hom.: 2495 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.192 AC: 37975 AN: 198172 Hom.: 5235 AF XY: 0.181 AC XY: 19371 AN XY: 106902

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.508

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.141 AC: 201600 AN: 1429658 Hom.: 18406 Cov.: 38 AF XY: 0.141 AC XY: 99713 AN XY: 708132

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.495

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.118

Gnomad4 OTH exome AF: 0.159

GnomAD4 genome AF: 0.159 AC: 24186 AN: 152218 Hom.: 2502 Cov.: 33 AF XY: 0.168 AC XY: 12482 AN XY: 74422

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.507

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.181

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.157

Alfa AF: 0.123 Hom.: 3086

Bravo AF: 0.167

TwinsUK AF: 0.117 AC: 434

ALSPAC AF: 0.113 AC: 434

ESP6500AA AF: 0.137 AC: 566

ESP6500EA AF: 0.115 AC: 967

ExAC AF: 0.157 AC: 18807

Asia WGS AF: 0.299 AC: 1039 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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	Gly2018Arg in Exon 28 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 13.7% (472/3448) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs2272571). -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

Benign, 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 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	7.8
Dann	Benign	0.73
DEOGEN2	Benign	0.0022	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.52	T;.;T
MetaRNN	Benign	0.000091	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	.;B;B
Vest4		0.059
MutPred		0.23		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
ClinPred		0.00029	T
GERP RS		2.7
Varity_R		0.029
gMVP		0.22

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: rs2272571; hg19: chr17-18047189; COSMIC: COSV52753045; COSMIC: COSV52753045;