NM_000260.4:c.1591C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000260.4(MYO7A):​c.1591C>T​(p.Gln531*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,664 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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 5.66

Publications

2 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 11-77162889-C-T is Pathogenic according to our data. Variant chr11-77162889-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 553105.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO7ANM_000260.4 linkc.1591C>T p.Gln531* stop_gained Exon 14 of 49 ENST00000409709.9 NP_000251.3 Q13402-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYO7AENST00000409709.9 linkc.1591C>T p.Gln531* stop_gained Exon 14 of 49 1 NM_000260.4 ENSP00000386331.3 Q13402-1
MYO7AENST00000458637.6 linkc.1591C>T p.Gln531* stop_gained Exon 14 of 49 1 ENSP00000392185.2 Q13402-2
MYO7AENST00000409619.6 linkc.1558C>T p.Gln520* stop_gained Exon 15 of 50 1 ENSP00000386635.2 Q13402-8

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
249266
AF XY:
0.0000148
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461664
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727122
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111848
Other (OTH)
AF:
0.00
AC:
0
AN:
60372
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000238
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000825
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Jul 27, 2017
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:1
Dec 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln531*) 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). This variant is present in population databases (rs781951909, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 18181211). ClinVar contains an entry for this variant (Variation ID: 553105). For these reasons, this variant has been classified as Pathogenic. -

Hearing loss, autosomal recessive Pathogenic:1
-
University of Washington Center for Mendelian Genomics, University of Washington
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
39
DANN
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
5.7
Vest4
0.90
GERP RS
4.8
Mutation Taster
=0/200
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs781951909; hg19: chr11-76873935; COSMIC: COSV108246602; API