rs1555102843

Positions:

• chr11-77202397-TGGA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000260.4(MYO7A):​c.5146_5148delGAG​(p.Glu1716del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,401,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: MYO7A NM_000260.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.83

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000260.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-77202397-TGGA-T is Pathogenic according to our data. Variant chr11-77202397-TGGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77202397-TGGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.5146_5148delGAG	p.Glu1716del	conservative_inframe_deletion	37/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.5146_5148delGAG	p.Glu1716del	conservative_inframe_deletion	37/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.5032_5034delGAG	p.Glu1678del	conservative_inframe_deletion	37/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4999_5001delGAG	p.Glu1667del	conservative_inframe_deletion	38/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2572_2574delGAG	p.Glu858del	conservative_inframe_deletion	17/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2986_2988delGAG		non_coding_transcript_exon_variant	20/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1401718 Hom.: 0 AF XY: 0.00000434 AC XY: 3 AN XY: 691612

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: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2008

- -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 27, 2023

Variant summary: MYO7A c.5146_5148delGAG (p.Glu1716del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant was absent in 159352 control chromosomes. c.5146_5148delGAG has been reported in the literature in multiple individuals affected with autosomal recessive non-syndromic congenital deafness with evidence of segregation (example: Riazuddin_2008). These data indicate that the variant is very likely to be associated with disease. GFP-myosin VIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfected mouse hair cells, suggesting potentially less severe phenotype (Riazuddin_2008). The following publication has been ascertained in the context of this evaluation (PMID: 18181211). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2+PP1_Strong+PM3 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555102843; hg19: chr11-76913442;