NM_000260.4:c.448C>T

Variant names:

• chr11-77156069-C-T
• rs121965079
• NM_000260.4:c.448C>T

Variant summary

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

The NM_000260.4(MYO7A):​c.448C>T​(p.Arg150*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,548 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R150R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYO7A NM_000260.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.44

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-77156069-C-T is Pathogenic according to our data. Variant chr11-77156069-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77156069-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.448C>T	p.Arg150*	stop_gained	Exon 5 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.448C>T	p.Arg150*	stop_gained	Exon 5 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.448C>T	p.Arg150*	stop_gained	Exon 5 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.415C>T	p.Arg139*	stop_gained	Exon 6 of 50	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461548 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727028

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: 0.0000232

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11847). This premature translational stop signal has been observed in individuals with autosomal recessive Usher syndrome (PMID: 7870171, 28451532). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg150*) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). -

Mar 20, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 16470552, 28451532, 31479088, 7568224, 7870171, 9002678, 20613545, 31054281, 33576163) -

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

May 25, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. (exon 5 of 9). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity (Decipher, ClinVar, Subira, O. et al. (2019), Bademci, G. et al. (2016)). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals with hearing loss and Usher syndrome (LOVD, ClinVar, Asgharzade, S. et al. (2017)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1201 - Heterozygous variant detected in trans with a second (at least likely) pathogenic heterozygous variant in a recessive disease. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Usher syndrome Pathogenic:1

Aug 13, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg150X variant in MYO7A has been previously reported in five individuals with Usher syndrome and one individual with sensorineural hearing loss who were either homozygous for the variant or harbored a second pathogenic MYO7A variant in trans (Jaijo 2006 PMID:16470552, Kimberling 2010 PMID:20613545, Nakanishi 2010 PMID:20844544, Asgharzade 2017 PMID:28451532, Ivanova 2018 PMID:30358468, Gao 2019 PMID:31054281, LMM unpublished data). It is absent from large population studies. This nonsense variant leads to a premature termination codon at position 150, which is predicted 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 summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PVS1, PM2, PM3, PP4. -

Usher syndrome type 1B Pathogenic:1

Oct 10, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.89
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121965079; hg19: chr11-76867115;