11-77180404-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000260.4(MYO7A):c.2617C>T(p.Arg873Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,611,950 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R873Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:4
• Conservation: PhyloP100: 3.76

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15834317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.2617C>T	p.Arg873Trp	missense_variant	22/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.2617C>T	p.Arg873Trp	missense_variant	22/49	1	NM_000260.4

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00102 AC: 251 AN: 245898 Hom.: 1 AF XY: 0.00115 AC XY: 154 AN XY: 134040

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00221

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.000836

GnomAD4 exome AF: 0.00119 AC: 1743 AN: 1459682 Hom.: 1 Cov.: 32 AF XY: 0.00117 AC XY: 852 AN XY: 725980

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00246

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000900 AC XY: 67 AN XY: 74446

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000735 AC: 3

ESP6500EA AF: 0.000719 AC: 6

ExAC AF: 0.00134 AC: 161

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2022	Identified in the heterozygous state in individuals with Usher syndrome or hearing loss as well as unaffected members of some families, and no second pathogenic variant was reported in the affected individuals (Kothiyal et al., 2010; Vastinsalo et al., 2013; Zazo Seco et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22135276, 21487335, 23891399, 20146813, 30245029, 34426522, 28000701, 22681893, 34391192) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

Autosomal dominant nonsyndromic hearing loss 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 20, 2018	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_000260.3(MYO7A):c.2617C>T(R873W) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. R873W has been observed in cases with relevant disease (PMID: 22681893, 20146813, 28000701). Functional assessments of this variant are not available in the literature. R873W has been observed in population frequency databases (gnomAD: FIN 0.23%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.2617C>T(R873W) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Meniere disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Dec 14, 2020

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 09, 2012

p.Arg873Trp in exon 22 of MYO7A: This variant has been reported in 4 individual s with sensorineural hearing loss or Usher syndrome; however, none of these indi viduals had a second MYO7A variant (Saihan 2011, Kothiyal 2010, Strike 2008). Th is variant has also been identified in 0.2% (141/62260) of European chromosomes including 1 homozygote by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs200454015). Based upon identification in 0.2% of contr ols and not identifying a second MYO7A variant in any affected individuals, this variant is likely benign. -

Usher syndrome type 1B Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T;.;.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.2	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.9	D;.;D;D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0070	D;.;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;.;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.91
MVP		0.96
MPC		0.47
ClinPred		0.11	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.55

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: rs200454015; hg19: chr11-76891450;