chr11-77166091-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_ModerateBP6BS1

The NM_000260.4(MYO7A):​c.1726G>A​(p.Asp576Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000775 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

6
6
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 6.92
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 Likely_benign. Variant got -5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11430189).
BP6
Variant 11-77166091-G-A is Benign according to our data. Variant chr11-77166091-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164674.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000445 (65/1461634) while in subpopulation AFR AF= 0.00167 (56/33474). AF 95% confidence interval is 0.00132. There are 0 homozygotes in gnomad4_exome. There are 24 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYO7ANM_000260.4 linkc.1726G>A p.Asp576Asn missense_variant 15/49 ENST00000409709.9 NP_000251.3 Q13402-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYO7AENST00000409709.9 linkc.1726G>A p.Asp576Asn missense_variant 15/491 NM_000260.4 ENSP00000386331.3 Q13402-1
MYO7AENST00000458637.6 linkc.1726G>A p.Asp576Asn missense_variant 15/491 ENSP00000392185.2 Q13402-2
MYO7AENST00000409619.6 linkc.1693G>A p.Asp565Asn missense_variant 16/501 ENSP00000386635.2 Q13402-8
MYO7AENST00000669443.1 linkc.34G>A p.Asp12Asn missense_variant 1/3 ENSP00000499530.1 A0A590UJR8

Frequencies

GnomAD3 genomes
AF:
0.000401
AC:
61
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00140
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000108
AC:
27
AN:
249102
Hom.:
0
AF XY:
0.0000814
AC XY:
11
AN XY:
135158
show subpopulations
Gnomad AFR exome
AF:
0.00142
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000445
AC:
65
AN:
1461634
Hom.:
0
Cov.:
31
AF XY:
0.0000330
AC XY:
24
AN XY:
727088
show subpopulations
Gnomad4 AFR exome
AF:
0.00167
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000394
AC:
60
AN:
152280
Hom.:
0
Cov.:
32
AF XY:
0.000416
AC XY:
31
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.00137
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000854
Hom.:
0
Bravo
AF:
0.000385
ESP6500AA
AF:
0.000995
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000124
AC:
15
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 06, 2013Variant classified as Uncertain Significance - Favor Benign. The Asp576Asn varia nt in MYO7A has not been previously reported in individuals with hearing loss, b ut has been identified in 0.1% (4/4022) of African American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs187165 412). Although this variant has been seen in the general population, its frequen cy is not high enough to rule out a pathogenic role. Computational analyses (bi ochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) d o not provide strong support for or against an impact to the protein. In summary , additional information is needed to determine the clinical significance of th is variant.. -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 28, 2023In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 21, 2025- -
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylApr 20, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D;T;.;.
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D
M_CAP
Benign
0.055
D
MetaRNN
Benign
0.11
T;T;T;T
MetaSVM
Uncertain
-0.063
T
MutationAssessor
Benign
1.6
L;.;L;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-4.3
D;.;D;D
REVEL
Uncertain
0.51
Sift
Benign
0.033
D;.;D;D
Sift4G
Uncertain
0.058
T;T;T;T
Polyphen
1.0
D;.;.;.
Vest4
0.64
MVP
0.91
MPC
0.46
ClinPred
0.12
T
GERP RS
5.5
Varity_R
0.53
gMVP
0.66

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: rs187165412; hg19: chr11-76877137; API