11-77130637-G-A

Position:

• chr11-77130637-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000260.4(MYO7A):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000479 in 1,461,006 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MYO7A NM_000260.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.05

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000260.4 (MYO7A) was described as [Likely_pathogenic] in ClinVar as 179567
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-77130637-G-A is Pathogenic according to our data. Variant chr11-77130637-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77130637-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4	c.3G>A	p.Met1?	start_lost	2/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.3G>A	p.Met1?	start_lost	2/49	1	NM_000260.4
MYO7A	ENST00000458637.6	c.3G>A	p.Met1?	start_lost	2/49	1		P1
MYO7A	ENST00000409619.6	c.-111G>A		5_prime_UTR_variant	2/50	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247242 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134194

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461006 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Aug 08, 2017

- -

Usher syndrome type 1B Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 16, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

This sequence change affects the initiator methionine of the MYO7A mRNA. The next in-frame methionine is located at codon 12. This variant is present in population databases (rs782787126, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with autosomal recessive Usher syndrome or retinitis pigmentosa (PMID: 30459346; Invitae). ClinVar contains an entry for this variant (Variation ID: 553231). This variant disrupts the p.Gly7 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30303587). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Meniere disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

case-control

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Dec 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;.
Eigen	Benign	0.086
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-1.7	N;.;N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0080	D;.;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.10	B;.;.
Vest4		0.85
MutPred		0.93		Gain of catalytic residue at M1 (P = 0.0676);Gain of catalytic residue at M1 (P = 0.0676);Gain of catalytic residue at M1 (P = 0.0676);
MVP		0.91
ClinPred		0.62	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782787126; hg19: chr11-76841683;