rs876657713

Variant names:

• chr11-77207388-AAAATTGCAGAC-A
• rs876657713
• NM_000260.4:c.5845_5855delATTGCAGACAA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_000260.4(MYO7A):​c.5845_5855delATTGCAGACAA​(p.Ile1949GlyfsTer6) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYO7A NM_000260.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.87
• Publications: 0 publications found

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]

MYO7A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-77207388-AAAATTGCAGAC-A is Pathogenic according to our data. Variant chr11-77207388-AAAATTGCAGAC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 228380.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5845_5855delATTGCAGACAA	p.Ile1949GlyfsTer6	frameshift_variant, splice_region_variant	Exon 42 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5845_5855delATTGCAGACAA	p.Ile1949GlyfsTer6	frameshift_variant, splice_region_variant	Exon 42 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5731_5741delATTGCAGACAA	p.Ile1911GlyfsTer6	frameshift_variant, splice_region_variant	Exon 42 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.5698_5708delATTGCAGACAA	p.Ile1900GlyfsTer6	frameshift_variant, splice_region_variant	Exon 43 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.3271_3281delATTGCAGACAA	p.Ile1091GlyfsTer6	frameshift_variant, splice_region_variant	Exon 22 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.*443_*453delATTGCAGACAA		splice_region_variant, non_coding_transcript_exon_variant	Exon 25 of 32			ENSP00000499323.1
MYO7A	ENST00000670577.1	n.*443_*453delATTGCAGACAA		3_prime_UTR_variant	Exon 25 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

May 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile1949fs variant in MYO7A has not been previously reported in individuals with hearing loss or Usher syndrome. It has not been identified in large popul ation studies, though the ability of these studies to accurately detect indels m ay be limited. This variant is predicted to cause a frameshift, which alters th e protein?s amino acid sequence beginning at position 1949 and leads to a premat ure termination codon 6 amino acids downstream. This alteration is then predicte d to lead to a truncated or absent protein. Loss of function of the MYO7A gene is an established disease mechanism in autosomal recessive Usher syndrome. In s ummary, this variant meets our criteria to be classified as pathogenic for autos omal recessive Usher syndrome (www.partners.org/personalizedmedicine/lmm), based on the predicted impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs876657713; hg19: chr11-76918433;