rs111033233

Variant names:

• chr11-77181589-G-A
• rs111033233
• NM_000260.4:c.2904G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77181589-G-A
• chr11-77181589-G-T

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.2904G>A​(p.Glu968Glu) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO7A NM_000260.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:2
• Conservation: PhyloP100: 6.16

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-77181589-G-A is Pathogenic according to our data. Variant chr11-77181589-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.2904G>A	p.Glu968Glu	splice_region_variant, synonymous_variant	Exon 23 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.2904G>A	p.Glu968Glu	splice_region_variant, synonymous_variant	Exon 23 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.2904G>A	p.Glu968Glu	splice_region_variant, synonymous_variant	Exon 23 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.2871G>A	p.Glu957Glu	splice_region_variant, synonymous_variant	Exon 24 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.447G>A	p.Glu149Glu	splice_region_variant, synonymous_variant	Exon 3 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.744G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247002 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 968 of the MYO7A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYO7A protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs111033233, gnomAD 0.006%). This variant has been observed in individual(s) with clinical features of Usher syndrome (PMID: 36164746; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228280). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 23, but is expected to preserve the integrity of the reading-frame (PMID: 36164746). This variant disrupts the c.2904G nucleotide in the MYO7A gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10930322, 15660226, 24199935, 25472526, 26969326). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1

Aug 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2904G>A (p.Glu968Glu) variant in MYO7A has not been previously reported in individuals with hearing loss, but has been identified in 1/8202 East Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg). Although this variant has been seen in the general population, its frequenc y is low enough to be consistent with a recessive carrier frequency. This varian t is located at the last base of the exon, which is a highly conserved nucleotid e that is part of the 5' splice region. Computational tools predict that this v ariant is likely to impact splicing. In addition, a pathogenic variant affectin g the same nucleotide position (c.2904G>T, p.Glu968Asp) has been reported in 7 i ndividuals with Usher syndrome, including one homozygote and five compound heter ozygotes (Bharadwaj 2000, Ouyang 2005, Jacobson 2008, Le Quesne Stabej 2012, Buj akowska 2014, LMM unpublished data). In summary, although additional studies, s uch as functional analysis, are required to fully establish its clinical signifi cance, this variant is likely pathogenic. -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1

Jan 24, 2019

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1 Uncertain:1

Jan 24, 2019

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: -44
DS_DL_spliceai		0.94		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033233; hg19: chr11-76892635;