rs782485961

chr11-77174804-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000260.4(MYO7A):c.1984A>T(p.Met662Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,611,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.94

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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000260.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.1984A>T	p.Met662Leu	missense_variant	17/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.1984A>T	p.Met662Leu	missense_variant	17/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.1984A>T	p.Met662Leu	missense_variant	17/49	1		P1
MYO7A	ENST00000409619.6	c.1951A>T	p.Met651Leu	missense_variant	18/50	1
MYO7A	ENST00000409893.6	c.49A>T	p.Met17Leu	missense_variant	1/11	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000123 AC: 3 AN: 244610 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459714 Hom.: 0 Cov.: 34 AF XY: 0.00000827 AC XY: 6 AN XY: 725934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.00000756

ExAC AF: 0.0000249 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 03, 2022	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 662 of the MYO7A protein (p.Met662Leu). This variant is present in population databases (rs782485961, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 517510). 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 not expected to disrupt 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 17, 2020	The p.Met662Leu variant in MYO7A has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in .01% (2/19358) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs782485961). This variant has also been reported in ClinVar (Variation ID 517510). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting. -

Usher syndrome type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.80	D;T;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Uncertain	0.026	D
MutationAssessor	Benign	-0.23	N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D;.;D;D;.
REVEL	Pathogenic	0.73
Sift	Benign	0.039	D;.;D;D;.
Sift4G	Benign	0.23	T;T;T;T;.
Polyphen		0.41	B;.;.;.;.
Vest4		0.83
MutPred		0.72		Loss of MoRF binding (P = 0.0848);Loss of MoRF binding (P = 0.0848);Loss of MoRF binding (P = 0.0848);.;.;
MVP		0.79
MPC		0.43
ClinPred		0.80	D
GERP RS		5.2
Varity_R		0.53
gMVP		0.69

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: rs782485961; hg19: chr11-76885850;