11-77198503-C-T

Position:

• chr11-77198503-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000260.4(MYO7A):​c.4450C>T​(p.Leu1484Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,613,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 O:1
• Conservation: PhyloP100: 3.45

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]

MYO7A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4450C>T	p.Leu1484Phe	missense_variant	34/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4450C>T	p.Leu1484Phe	missense_variant	34/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4450C>T	p.Leu1484Phe	missense_variant	34/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4417C>T	p.Leu1473Phe	missense_variant	35/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1993C>T	p.Leu665Phe	missense_variant	14/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2290C>T		non_coding_transcript_exon_variant	17/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000563 AC: 14 AN: 248864 Hom.: 0 AF XY: 0.0000666 AC XY: 9 AN XY: 135088

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461406 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 726968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 1

Bravo AF: 0.000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000360 AC: 3

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1 Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 05, 2024	This variant was identified as compound-heterozygous with NM_000260.3:c.3283G>A, p.(Glu1095Lys). The variant has often been identified in individuals with autosomal recessive Usher Syndrome (PMID: 16470552, 30245029, 31964843, 33576163, 36672771). In silico predictions suggest a pathogenic effect. The variant has not been observed as homozygous in the general population (gnomAD). It is therefore classified as likely pathogenic with the following ACMG criteria applied: PM3_STR, PM2_SUP, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_000260.3(MYO7A):c.4450C>T(L1484F) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. L1484F has been observed in cases with relevant disease (PMID: 16470552). Functional assessments of this variant are not available in the literature. L1484F has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.4450C>T(L1484F) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 21, 2017	The MYO7A gene is one of at least nine genes in which variants are known to cause Usher syndrome and this gene is associated with Usher syndrome type 1 (USH1) and Usher syndrome type 2 (USH2). The c.4450C>T (p.Leu1484Phe) variant has been reported in a compound heterozygous state with a second missense variant in a Spanish individual with USH1 (Jaijo et al. 2006). The p.Leu1484Phe variant was shown to be absent from 100 control chromosomes and is reported at a frequency of 0.000360 in the European American population of the Exome Sequencing Project. It is predicted to affect the structure of the protein as it occurs in the folding core of the FERM domain (Wu et al. 2011); however, functional studies of its effects have not been conducted. The evidence for this variant is limited. The p.Leu1484Phe variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Uncertain:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Likely pathogenic and reported on 09-23-2014 by Fulgent Diagnostics . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 02, 2022	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1484 of the MYO7A protein (p.Leu1484Phe). This variant is present in population databases (rs200416912, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 16470552). ClinVar contains an entry for this variant (Variation ID: 43241). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO7A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2024	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: 30245029, 34426522, 16470552, 33671976, 33576163, 36672771) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 11, 2013

The Leu1484Phe variant in MYO7A has been reported in one individual with the cli nical features of Usher syndome type I who carried a second missense variant in MYO7A (Jaijo 2006), but has not been identified in any additional affected indiv iduals. However, this variant has been seen in 0.04% (3/8342) of European Americ an chromosomes in a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs200316912); though this frequency is not h igh enough to rule out a pathogenic rule. Computational analyses (biochemical am ino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provid e strong support for or against an impact to the protein. In summary, additional information is needed to determine the clinical significance of this variant. -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 26, 2018

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal dominant nonsyndromic hearing loss 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 26, 2018

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Usher syndrome type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.91	P;.;.;.
Vest4		0.85
MVP		0.95
MPC		0.40
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.59
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: rs200416912; hg19: chr11-76909548; COSMIC: COSV68686367; COSMIC: COSV68686367;