3-46701521-G-T

Position:

chr3-46701521-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_147196.3(TMIE):c.34G>T(p.Val12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,323,576 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

TMIE
NM_147196.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.94

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.112941355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMIE	NM_147196.3 linkuse as main transcript	c.34G>T	p.Val12Leu	missense_variant	1/4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1 linkuse as main transcript	c.-66-4269G>T		intron_variant			NP_001357453.1
TMIE	NM_001370525.1 linkuse as main transcript	c.-66-4269G>T		intron_variant			NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3 linkuse as main transcript	c.34G>T	p.Val12Leu	missense_variant	1/4		NM_147196.3	ENSP00000494576	P1
TMIE	ENST00000644830.1 linkuse as main transcript	c.-66-4269G>T		intron_variant				ENSP00000495111

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000279

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

155

AN:

1171398

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

563850

show subpopulations

Gnomad4 AFR exome

AF:

0.0000426

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000363

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.000104

GnomAD4 genome

AF:

0.000138

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000428

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 12 of the TMIE protein (p.Val12Leu). This variant is present in population databases (rs397517867, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TMIE-related conditions. ClinVar contains an entry for this variant (Variation ID: 47959). 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: "Tolerated"; PolyPhen-2: "Not Available"; 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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 08, 2015

The p.Val12Leu variant in TMIE has now been identified by our laboratory in the heterozygous state in 2 individuals with hearing loss; however, a variant affect ing the other copy of the TMIE gene has not been identified in either of them. D ata from large population studies are insufficient to assess the frequency of th is variant in the general population. Computational prediction tools and conserv ation analysis suggest that the p.Val12Leu variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, the clinical significance of the p.Val12Leu variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2022

The c.34G>T (p.V12L) alteration is located in exon 1 (coding exon 1) of the TMIE gene. This alteration results from a G to T substitution at nucleotide position 34, causing the valine (V) at amino acid position 12 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.070

T;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.71

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.41

.;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.15

.;N

REVEL

Benign

0.24

Sift

Benign

0.14

.;T

Sift4G

Benign

0.73

.;T

Polyphen

0.0

B;B

Vest4

0.16

MutPred

0.25

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.27

MPC

0.28

ClinPred

0.073

GERP RS

2.3

Varity_R

0.070

gMVP

0.40

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.

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