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GeneBe

rs41298757

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000260.4(MYO7A):​c.6240C>T​(p.Ser2080=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,613,416 control chromosomes in the GnomAD database, including 1,124 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 64 hom., cov: 32)
Exomes 𝑓: 0.035 ( 1060 hom. )

Consequence

MYO7A
NM_000260.4 splice_region, synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.610
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-77211823-C-T is Benign according to our data. Variant chr11-77211823-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77211823-C-T is described in Lovd as [Benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.61 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.025 (3807/152284) while in subpopulation NFE AF= 0.0411 (2798/68010). AF 95% confidence interval is 0.0399. There are 64 homozygotes in gnomad4. There are 1796 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYO7ANM_000260.4 linkuse as main transcriptc.6240C>T p.Ser2080= splice_region_variant, synonymous_variant 46/49 ENST00000409709.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYO7AENST00000409709.9 linkuse as main transcriptc.6240C>T p.Ser2080= splice_region_variant, synonymous_variant 46/491 NM_000260.4 Q13402-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0250
AC:
3803
AN:
152166
Hom.:
64
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00746
Gnomad AMI
AF:
0.0351
Gnomad AMR
AF:
0.0189
Gnomad ASJ
AF:
0.0184
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.0182
Gnomad FIN
AF:
0.0136
Gnomad MID
AF:
0.0411
Gnomad NFE
AF:
0.0411
Gnomad OTH
AF:
0.0316
GnomAD3 exomes
AF:
0.0258
AC:
6438
AN:
249220
Hom.:
136
AF XY:
0.0275
AC XY:
3719
AN XY:
135150
show subpopulations
Gnomad AFR exome
AF:
0.00698
Gnomad AMR exome
AF:
0.0132
Gnomad ASJ exome
AF:
0.0180
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.0219
Gnomad FIN exome
AF:
0.0137
Gnomad NFE exome
AF:
0.0404
Gnomad OTH exome
AF:
0.0275
GnomAD4 exome
AF:
0.0345
AC:
50467
AN:
1461132
Hom.:
1060
Cov.:
31
AF XY:
0.0345
AC XY:
25087
AN XY:
726882
show subpopulations
Gnomad4 AFR exome
AF:
0.00654
Gnomad4 AMR exome
AF:
0.0140
Gnomad4 ASJ exome
AF:
0.0169
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0212
Gnomad4 FIN exome
AF:
0.0145
Gnomad4 NFE exome
AF:
0.0400
Gnomad4 OTH exome
AF:
0.0302
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0250
AC:
3807
AN:
152284
Hom.:
64
Cov.:
32
AF XY:
0.0241
AC XY:
1796
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.00746
Gnomad4 AMR
AF:
0.0189
Gnomad4 ASJ
AF:
0.0184
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.0184
Gnomad4 FIN
AF:
0.0136
Gnomad4 NFE
AF:
0.0411
Gnomad4 OTH
AF:
0.0318
Alfa
AF:
0.0333
Hom.:
75
Bravo
AF:
0.0242
Asia WGS
AF:
0.0100
AC:
35
AN:
3478
EpiCase
AF:
0.0454
EpiControl
AF:
0.0462

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 26, 2018- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 25, 2023- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 19, 2008- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 13, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Autosomal dominant nonsyndromic hearing loss 11 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Autosomal recessive nonsyndromic hearing loss 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Usher syndrome type 1B Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Usher syndrome type 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
CADD
Benign
1.2
DANN
Benign
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs41298757; hg19: chr11-76922868; API