rs201540919

chr17-18149328-G-A

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.7069G>A(p.Gly2357Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,611,674 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (1 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.920

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 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=0.007964015).
• BP6: Variant 17-18149328-G-A is Benign according to our data. Variant chr17-18149328-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227649.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.7069G>A	p.Gly2357Ser	missense_variant	34/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.7072G>A	p.Gly2358Ser	missense_variant	32/64
MYO15A	XM_017024714.3	c.7009G>A	p.Gly2337Ser	missense_variant	31/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.7069G>A	p.Gly2357Ser	missense_variant	34/66		NM_016239.4	P1
MYO15A	ENST00000578999.1	n.581G>A		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000180 AC: 44 AN: 244232 Hom.: 0 AF XY: 0.000219 AC XY: 29 AN XY: 132578

Gnomad AFR exome AF: 0.000667

Gnomad AMR exome AF: 0.000265

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000666

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000898 AC: 131 AN: 1459466 Hom.: 1 Cov.: 33 AF XY: 0.0000978 AC XY: 71 AN XY: 725918

Gnomad4 AFR exome AF: 0.000928

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74426

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000434

ESP6500AA AF: 0.000243 AC: 1

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000116 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2018	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.7069G>A (p.G2357S) alteration is located in exon 34 (coding exon 33) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 7069, causing the glycine (G) at amino acid position 2357 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 17, 2015

p.Gly2357Ser in exon 34 of MYO15A: This variant is not expected to have clinical significance because the glycine (Gly) residue at position 2357 is not conserve d through species, with 10 mammals having a serine (Ser) at this position. It ha s been identified in 14/104260 chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs201540919). -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.7
Dann	Benign	0.84
DEOGEN2	Benign	0.0051	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.54	T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.12	T;T;.
Polyphen		0.0030	.;B;B
Vest4		0.13
MVP		0.33
ClinPred		0.011	T
GERP RS		-4.4
Varity_R		0.042
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201540919; hg19: chr17-18052642;