3-46705887-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBS1_Supporting

The NM_147196.3(TMIE):c.191C>T(p.Ser64Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000366 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

TMIE
NM_147196.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 6.51

Variant links:

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]

TMIE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a chain Transmembrane inner ear expressed protein (size 128) in uniprot entity TMIE_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_147196.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.083521634).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000372 (544/1461786) while in subpopulation MID AF= 0.00711 (41/5768). AF 95% confidence interval is 0.00539. There are 1 homozygotes in gnomad4_exome. There are 290 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3 link	c.191C>T	p.Ser64Leu	missense_variant	Exon 2 of 4	ENST00000643606.3	NP_671729.2	Q8NEW7
TMIE	NM_001370524.1 link	c.32C>T	p.Ser11Leu	missense_variant	Exon 2 of 4		NP_001357453.1
TMIE	NM_001370525.1 link	c.32C>T	p.Ser11Leu	missense_variant	Exon 3 of 5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	ENST00000643606.3 link	c.191C>T	p.Ser64Leu	missense_variant	Exon 2 of 4	NM_147196.3	ENSP00000494576.2	Q8NEW7
TMIE	ENST00000644830.1 link	c.32C>T	p.Ser11Leu	missense_variant	Exon 2 of 4		ENSP00000495111.1	A0A2R8YDZ8
TMIE	ENST00000651652.1 link	c.89C>T	p.Ser30Leu	missense_variant	Exon 1 of 2		ENSP00000498953.1	A0A494C1A3

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000368

AC:

AN:

249670

Hom.:

AF XY:

0.000443

AC XY:

AN XY:

135418

show subpopulations

Gnomad AFR exome

AF:

0.000193

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000450

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.000372

AC:

544

AN:

1461786

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

290

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000371

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000309

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000386

Hom.:

Bravo

AF:

0.000283

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000379

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 64 of the TMIE protein (p.Ser64Leu). This variant is present in population databases (rs189895472, gnomAD 0.06%). This missense change has been observed in individual(s) with deafness (PMID: 24875298). ClinVar contains an entry for this variant (Variation ID: 165460). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 10, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24875298) -

Autosomal recessive nonsyndromic hearing loss 6

Uncertain:2

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. -

Mar 18, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TMIE c.191C>T; p.Ser64Leu variant (rs189895472) was detected in a patient with recessive hereditary hearing loss in the heterozygous state; however, a likely causative variant in another gene was also identified (Vona 2014). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.04% (identified on 105 out of 281,070 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 165460). The serine at position 64 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Ser64Leu variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Ser64Leu variant cannot be determined with certainty. -

not specified

Uncertain:1

Sep 11, 2016

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.Ser64Leu vari ant in TMIE has been previously reported in the heterozygous state in four indiv iduals with hearing loss; however, an alternate explanation of the hearing loss was identified in two of these individuals (Vona 2014, LMM data). This variant h as been identified across several populations by the Exome Aggregation Consortiu m with a frequency of 0.04% (46/120742) of the total chromosomes (ExAC, http://e xac.broadinstitute.org; dbSNP rs189895472). However, its frequency is not high e nough to rule out a pathogenic role. Computational prediction tools and conserva tion analyses do not provide strong support for or against an impact to the prot ein. In summary, while the clinical significance of the p.Ser64Leu variant is un certain, the identification of the variant in several individuals with an altern ate explanation of the hearing loss suggests it is more likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.084

T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

0.83

.;L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.40

.;.;N

REVEL

Uncertain

0.48

Sift

Benign

0.50

.;.;T

Sift4G

Uncertain

0.041

.;.;D

Polyphen

0.99

.;D;D

Vest4

0.49

MVP

0.90

MPC

0.52

ClinPred

0.035

GERP RS

5.2

Varity_R

0.16

gMVP

0.81

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over