chr3-46701579-A-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_147196.3(TMIE):c.92A>G(p.Glu31Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000936 in 1,281,500 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000088 ( 0 hom. )
Consequence
TMIE
NM_147196.3 missense, splice_region
NM_147196.3 missense, splice_region
Scores
1
9
4
Splicing: ADA: 0.9992
2
Clinical Significance
Conservation
PhyloP100: 2.66
Genes affected
TMIE (HGNC:30800): (transmembrane inner ear) This gene encodes a transmembrane inner ear protein. Studies in mouse suggest that this gene is required for normal postnatal maturation of sensory hair cells in the cochlea, including correct development of stereocilia bundles. This gene is one of multiple genes responsible for recessive non-syndromic deafness (DFNB), also known as autosomal recessive nonsyndromic hearing loss (ARNSHL), the most common form of congenitally acquired inherited hearing impairment. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 3-46701579-A-G is Pathogenic according to our data. Variant chr3-46701579-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46701579-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMIE | NM_147196.3 | c.92A>G | p.Glu31Gly | missense_variant, splice_region_variant | 1/4 | ENST00000643606.3 | |
TMIE | NM_001370524.1 | c.-66-4211A>G | intron_variant | ||||
TMIE | NM_001370525.1 | c.-66-4211A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMIE | ENST00000643606.3 | c.92A>G | p.Glu31Gly | missense_variant, splice_region_variant | 1/4 | NM_147196.3 | P1 | ||
TMIE | ENST00000644830.1 | c.-66-4211A>G | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151356Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000885 AC: 10AN: 1130144Hom.: 0 Cov.: 30 AF XY: 0.00000928 AC XY: 5AN XY: 538700
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 16, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 372538). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 16389551, 24416283). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 31 of the TMIE protein (p.Glu31Gly). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2015 | The E31G pathogenic variant in the TMIE gene has been reported previously in several individuals with hearing loss who were homozygous for this variant (Santos et al., 2006; Ganapathy et al., 20140. The E31G variant was not observed in approximately 4,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E31G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E31G as a pathogenic variant. - |
Autosomal recessive nonsyndromic hearing loss 6 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.E31G in TMIE (NM_147196.2) has been previously reported in homozygous form in patients affected with sensorineural hearing loss including those of Indian origin (Santos et al, 2006; Ganapathy et al, 2014). The variant has been submiited to ClinVar as Pathogenic but no functional studies have been performed. The p.E31G variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between glutamic acid and glycine. In silico analsyis predict a damaging effect while the residue is semi-conserved across species. For these reasons, this variant has been classified as Likely Pathogenic - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Polyphen
D;D
Vest4
0.73
MutPred
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP
0.82
MPC
0.47
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -35
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at