chr3-46709583-T-G

Position:

chr3-46709583-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_147196.3(TMIE):c.366T>G(p.Asp122Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000094 in 1,552,542 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

TMIE
NM_147196.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -2.19

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.

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=0.03653851).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMIE	NM_147196.3 linkuse as main transcript	c.366T>G	p.Asp122Glu	missense_variant	4/4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1 linkuse as main transcript	c.207T>G	p.Asp69Glu	missense_variant	4/4		NP_001357453.1
TMIE	NM_001370525.1 linkuse as main transcript	c.207T>G	p.Asp69Glu	missense_variant	5/5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
TMIE	ENST00000643606.3 linkuse as main transcript	c.366T>G	p.Asp122Glu	missense_variant	4/4	NM_147196.3	ENSP00000494576	P1
TMIE	ENST00000644830.1 linkuse as main transcript	c.207T>G	p.Asp69Glu	missense_variant	4/4		ENSP00000495111
TMIE	ENST00000651652.1 linkuse as main transcript	c.*288T>G		3_prime_UTR_variant	2/2		ENSP00000498953

Frequencies

GnomAD3 genomes

AF:

0.0000467

AC:

AN:

149950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000981

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000741

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

145554

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

78324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000267

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:

0.000196

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000991

AC:

139

AN:

1402592

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

698904

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.0000861

GnomAD4 genome

AF:

0.0000467

AC:

AN:

149950

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

73004

show subpopulations

Gnomad4 AFR

AF:

0.0000246

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000981

Gnomad4 NFE

AF:

0.0000741

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000745

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in a patient with autism spectrum disorder and reported to be de novo in published literature (PMID: 28714951); This variant is associated with the following publications: (PMID: 28714951) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2021	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 47960). This variant has not been reported in the literature in individuals affected with TMIE-related conditions. This variant is present in population databases (rs370899710, ExAC 0.01%). This sequence change replaces aspartic acid with glutamic acid at codon 122 of the TMIE protein (p.Asp122Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. -

Autosomal recessive nonsyndromic hearing loss 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 15, 2013

Asp122Glu in exon 4 of TMIE: This variant is not expected to have clinical signi ficance because this amino acid is not evolutionarily conserved with several mam mals, including rabbit, cat, and cow, carrying a glutamic acid (Glu) at this pos ition. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.14

DANN

Benign

0.95

DEOGEN2

Benign

0.41

.;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0087

LIST_S2

Benign

0.16

T;.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.69

.;N;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.86

.;.;N

REVEL

Benign

0.23

Sift

Benign

0.38

.;.;T

Sift4G

Benign

0.57

.;.;T

Polyphen

0.0

.;B;B

Vest4

0.10

MutPred

0.094

.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.39

MPC

0.26

ClinPred

0.055

GERP RS

-8.9

Varity_R

0.037

gMVP

0.0088

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