rs397516286

chr11-77162272-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000260.4(MYO7A):c.1496T>C(p.Ile499Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,402,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I499I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.1496T>C	p.Ile499Thr	missense_variant	13/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.1496T>C	p.Ile499Thr	missense_variant	13/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.1496T>C	p.Ile499Thr	missense_variant	13/49	1		P1
MYO7A	ENST00000409619.6	c.1463T>C	p.Ile488Thr	missense_variant	14/50	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1402016 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 20, 2012

The Ile499Thr variant in MYO7A has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, conservation, PolyPhen2, and SIFT) suggest that the Ile499Thr var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 05, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2022

This variant is not present in population databases (gnomAD no frequency). 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. ClinVar contains an entry for this variant (Variation ID: 43149). This missense change has been observed in individual(s) with clinical features of MYO7A-related conditions (Invitae). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 499 of the MYO7A protein (p.Ile499Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.2	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.98
MutPred		0.90		Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);.;
MVP		0.92
MPC		0.52
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.84

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: rs397516286; hg19: chr11-76873318;