17-18121940-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016239.4(MYO15A):c.3140C>G(p.Pro1047Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,613,412 control chromosomes in the GnomAD database, including 29 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1047H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0072 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (20 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.701

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=0.0052706897).
• BP6: Variant 17-18121940-C-G is Benign according to our data. Variant chr17-18121940-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226783.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00716 (1090/152274) while in subpopulation AFR AF= 0.0163 (677/41560). AF 95% confidence interval is 0.0153. There are 9 homozygotes in gnomad4. There are 529 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.3140C>G	p.Pro1047Arg	missense_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.3140C>G	p.Pro1047Arg	missense_variant	2/66		NM_016239.4	P1
MYO15A	ENST00000583079.1	n.2773C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00699 AC: 1063 AN: 152156 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00353 AC: 879 AN: 249180 Hom.: 4 AF XY: 0.00347 AC XY: 470 AN XY: 135278

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000890

Gnomad SAS exome AF: 0.00324

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00373 AC: 5451 AN: 1461138 Hom.: 20 Cov.: 44 AF XY: 0.00373 AC XY: 2710 AN XY: 726868

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000806

Gnomad4 SAS exome AF: 0.00337

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00370

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.00716 AC: 1090 AN: 152274 Hom.: 9 Cov.: 33 AF XY: 0.00711 AC XY: 529 AN XY: 74452

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00743

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0152 AC: 60

ESP6500EA AF: 0.00432 AC: 36

ExAC AF: 0.00386 AC: 467

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00367

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain: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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 21, 2015

p.Pro1047Arg in exon 2 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 1.6% (159/9738) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs77565048). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	11
Dann	Benign	0.78
DEOGEN2	Benign	0.011	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.35	T;.;T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
Sift4G	Uncertain	0.0090	D;D;.
Polyphen		0.23	.;B;B
Vest4		0.15
MVP		0.45
ClinPred		0.028	T
GERP RS		2.5
Varity_R		0.054
gMVP		0.28

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: rs77565048; hg19: chr17-18025254;