rs397516317

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000260.4(MYO7A):​c.5392C>G​(p.Gln1798Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

6
7
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.47

Publications

8 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: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000260.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYO7ANM_000260.4 linkc.5392C>G p.Gln1798Glu missense_variant Exon 39 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.5392C>G p.Gln1798Glu missense_variant Exon 39 of 49 1 NM_000260.4 ENSP00000386331.3 Q13402-1
MYO7AENST00000458637.6 linkc.5278C>G p.Gln1760Glu missense_variant Exon 39 of 49 1 ENSP00000392185.2 Q13402-2
MYO7AENST00000409619.6 linkc.5245C>G p.Gln1749Glu missense_variant Exon 40 of 50 1 ENSP00000386635.2 Q13402-8
MYO7AENST00000458169.2 linkc.2818C>G p.Gln940Glu missense_variant Exon 19 of 29 1 ENSP00000417017.2 H7C4D8
MYO7AENST00000670577.1 linkn.3218C>G non_coding_transcript_exon_variant Exon 22 of 32 ENSP00000499323.1 A0A590UJ94

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1446396
Hom.:
0
Cov.:
30
AF XY:
0.00000139
AC XY:
1
AN XY:
718008
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33026
American (AMR)
AF:
0.00
AC:
0
AN:
42866
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25806
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38800
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83018
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52298
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5752
European-Non Finnish (NFE)
AF:
0.00000272
AC:
3
AN:
1104950
Other (OTH)
AF:
0.00
AC:
0
AN:
59880
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.408
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D;.;.;T
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.76
D;D;D;D
MetaSVM
Uncertain
0.42
D
MutationAssessor
Benign
0.94
L;.;.;.
PhyloP100
7.5
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-2.3
N;N;N;N
REVEL
Pathogenic
0.71
Sift
Benign
0.22
T;T;T;T
Sift4G
Benign
0.27
T;T;T;T
Polyphen
0.15
B;.;.;.
Vest4
0.87
MutPred
0.59
Gain of disorder (P = 0.0944);.;.;.;
MVP
0.94
MPC
0.48
ClinPred
0.97
D
GERP RS
4.7
Varity_R
0.70
gMVP
0.53
Mutation Taster
=43/57
disease causing

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

Other links and lift over

dbSNP: rs397516317; hg19: chr11-76915186; API