rs797044492

Positions:

• chr11-77162881-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000260.4(MYO7A):​c.1583T>G​(p.Leu528Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.49

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 11-77162881-T-G is Pathogenic according to our data. Variant chr11-77162881-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1583T>G	p.Leu528Arg	missense_variant	14/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1583T>G	p.Leu528Arg	missense_variant	14/49	1	NM_000260.4	ENSP00000386331
MYO7A	ENST00000458637.6	c.1583T>G	p.Leu528Arg	missense_variant	14/49	1		ENSP00000392185	P1
MYO7A	ENST00000409619.6	c.1550T>G	p.Leu517Arg	missense_variant	15/50	1		ENSP00000386635

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 09, 2019

The p.Leu528Arg variant in MYO7A has been identified by our laboratory in the homozygous state in 1 Lebanese individual with clinical features consistent with type 1 Usher syndrome (congenital profound sensorineural hearing loss, delayed walking, generalized retinal degeneration and night blindness). Both parents were heterozygous for the variant and the variant segregated in the homozygous state in an affected sibling. This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PM2, PP1, PP3, PP4, PM3_Supporting. -

Usher syndrome type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

King Laboratory, University of Washington

Aug 01, 2020

MYO7A c.1583T>G, p.L528R alters a highly conserved residue of MYO7A. The variant is compound heterozygous with MYO7A c.2630insG p.W2077fs in three Palestinian children with moderate to severe hearing loss and Usher syndrome type I (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.98
MutPred		0.88		Loss of ubiquitination at K527 (P = 0.0235);Loss of ubiquitination at K527 (P = 0.0235);Loss of ubiquitination at K527 (P = 0.0235);.;
MVP		0.97
MPC		0.56
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.95

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: rs797044492; hg19: chr11-76873927;