chr11-77202364-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000260.4(MYO7A):​c.5108C>T​(p.Ala1703Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000261 in 1,565,632 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1703E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2O:1

Conservation

PhyloP100: 1.55
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.021813035).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO7ANM_000260.4 linkc.5108C>T p.Ala1703Val missense_variant Exon 37 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.5108C>T p.Ala1703Val missense_variant Exon 37 of 49 1 NM_000260.4 ENSP00000386331.3 Q13402-1
MYO7AENST00000458637.6 linkc.4994C>T p.Ala1665Val missense_variant Exon 37 of 49 1 ENSP00000392185.2 Q13402-2
MYO7AENST00000409619.6 linkc.4961C>T p.Ala1654Val missense_variant Exon 38 of 50 1 ENSP00000386635.2 Q13402-8
MYO7AENST00000458169.2 linkc.2534C>T p.Ala845Val missense_variant Exon 17 of 29 1 ENSP00000417017.2 H7C4D8
MYO7AENST00000670577.1 linkn.2948C>T non_coding_transcript_exon_variant Exon 20 of 32 ENSP00000499323.1 A0A590UJ94

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
152064
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00317
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000338
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000259
AC:
45
AN:
173552
Hom.:
0
AF XY:
0.000270
AC XY:
25
AN XY:
92478
show subpopulations
Gnomad AFR exome
AF:
0.000105
Gnomad AMR exome
AF:
0.000493
Gnomad ASJ exome
AF:
0.00182
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000183
Gnomad OTH exome
AF:
0.000422
GnomAD4 exome
AF:
0.000253
AC:
358
AN:
1413450
Hom.:
1
Cov.:
30
AF XY:
0.000263
AC XY:
184
AN XY:
698608
show subpopulations
Gnomad4 AFR exome
AF:
0.0000309
Gnomad4 AMR exome
AF:
0.000847
Gnomad4 ASJ exome
AF:
0.00189
Gnomad4 EAS exome
AF:
0.0000270
Gnomad4 SAS exome
AF:
0.0000125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000236
Gnomad4 OTH exome
AF:
0.000290
GnomAD4 genome
AF:
0.000329
AC:
50
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.000336
AC XY:
25
AN XY:
74398
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000915
Gnomad4 ASJ
AF:
0.00317
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000363
Hom.:
0
Bravo
AF:
0.000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000119
AC:
1
ExAC
AF:
0.000136
AC:
16

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 10, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nov 22, 2014
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MYO7A-related disorder Benign:1Other:1
Feb 13, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

-
GenomeConnect - Invitae Patient Insights Network
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 08-21-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not specified Uncertain:1
Dec 21, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Ala1703Val va riant in MYO7A has been previously reported by our laboratory in the heterozygou s state in 2 individuals with hearing loss, but a variant affecting the remainin g copy of the gene was not identified in either and an alternate etiology was fo und in one of them. It has been identified in 0.18% (16/8844) of Ashkenazi Jewis h chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org/; dbSNP rs199561332) and is reported in ClinVar (variation ID: 43271) . Computational prediction tools and conservation analysis suggest that the p.Al a1703Val variant may not impact the protein, though this information is not pred ictive enough to rule out pathogenicity. In summary, while the clinical signific ance of the p.Ala1703Val variant is uncertain, these data suggest that it is mor e likely to be benign. ACMG/AMP Criteria applied: BP4. -

Autosomal dominant nonsyndromic hearing loss 11 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Usher syndrome type 1B Uncertain:1
Apr 17, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Usher syndrome type 1 Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
9.8
DANN
Uncertain
0.98
DEOGEN2
Benign
0.24
T;.;.;T
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.66
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.53
T;T;T;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.022
T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.0
L;.;.;.
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.92
N;N;N;N
REVEL
Benign
0.060
Sift
Benign
0.37
T;T;T;T
Sift4G
Benign
0.36
T;T;T;T
Polyphen
0.0010
B;.;.;.
Vest4
0.21
MVP
0.73
MPC
0.084
ClinPred
0.026
T
GERP RS
3.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.073
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199561332; hg19: chr11-76913409; API