rs111033415

Positions:

• chr11-77162118-A-G

Variant summary

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

The ENST00000409709.9(MYO7A):​c.1344-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,443,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYO7A ENST00000409709.9 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.32

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-77162118-A-G is Pathogenic according to our data. Variant chr11-77162118-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 43143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77162118-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1344-2A>G		splice_acceptor_variant		ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1344-2A>G		splice_acceptor_variant		1	NM_000260.4	ENSP00000386331
MYO7A	ENST00000409619.6	c.1311-2A>G		splice_acceptor_variant		1		ENSP00000386635
MYO7A	ENST00000458637.6	c.1344-2A>G		splice_acceptor_variant		1		ENSP00000392185	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1443116 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715696

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15823922, 31479088) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	This sequence change affects an acceptor splice site in intron 12 of the MYO7A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with autosomal recessive deafness and/or autosomal recessive Usher syndrome (PMID: 15823922, 26445815, 27460420). This variant is also known as c.1244-2A>G. ClinVar contains an entry for this variant (Variation ID: 43143). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 08, 2017

- -

Usher syndrome type 1B Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 25, 2021

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Jul 15, 2021

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria:The c.1344-2 A>G variant in MYO7A gene is absent from population databases meeting PM2. This type of variant is predicted to generate a lost of the aceptor splicing site in MYO7A gene affecting gene MYO7A, which is a known mechanism of disease, PVS1. The c.1344-2 A>G has been identified in trans with a pathogenic variant in an Ushers patient with altered balance (PMID:15823922). Besides, it was identified in homocygous state in two different families (one with severe-profound non-syndrmic hearing loss and the other with Usher Syndromce) and an sporadic case with Usher Syndrome; PMID: 26445815, 27460420.); PP4. In thi work, c.1344-2 A>G was detected in trans with a pathogenic variant in MYO7A gene in a child with non-syndormic hearing loss (ophtalmic features could appear in the youth); PM3_S. Taking into account all the information together: PM2, PVS1, PM3_S, PP4 the variant is classified as Pathogenics for non-syndromic hearing loss and Usher Syndrome. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 12, 2017

The c.1344-2A>G variant in MYO7A has been reported in four individuals with Ushe r syndrome (Maubaret 2005, LMM data). One of them was homozygous for the variant and three other individuals were compound heterozygous with a second pathogenic MYO7A variant. This variant has not been identified in large population studies . In addition, this variant occurs in the invariant region (+/- 1/2) of the spli ce consensus sequence and is predicted to cause altered splicing leading to an a bnormal or absent protein. In summary, this variant meets criteria to be classif ied as pathogenic for Usher syndrome in an autosomal recessive manner. -

Ear malformation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 12
DS_AL_spliceai		0.87		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033415; hg19: chr11-76873164;