rs878853378

chr11-77174796-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000260.4(MYO7A):c.1976C>A(p.Ser659Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000686 in 1,458,356 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.84

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-77174796-C-A is Pathogenic according to our data. Variant chr11-77174796-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 236487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.1976C>A	p.Ser659Ter	stop_gained	17/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.1976C>A	p.Ser659Ter	stop_gained	17/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.1976C>A	p.Ser659Ter	stop_gained	17/49	1		P1
MYO7A	ENST00000409619.6	c.1943C>A	p.Ser648Ter	stop_gained	18/50	1
MYO7A	ENST00000409893.6	c.41C>A	p.Ser14Ter	stop_gained	1/11	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000913

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458356 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725092

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Feb 01, 2017

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not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2023

This sequence change creates a premature translational stop signal (p.Ser659*) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with inherited retinal disease (PMID: 27208204, 31816670). ClinVar contains an entry for this variant (Variation ID: 236487). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.93
GERP RS		5.2

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: rs878853378; hg19: chr11-76885842; COSMIC: COSV68684040;