rs28942096

Positions:

chr3-46709155-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_147196.3(TMIE):c.241C>T(p.Arg81Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TMIE
NM_147196.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 5.63

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 Likely_pathogenic. Variant got 6 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMIE	NM_147196.3 linkuse as main transcript	c.241C>T	p.Arg81Cys	missense_variant	3/4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1 linkuse as main transcript	c.82C>T	p.Arg28Cys	missense_variant	3/4		NP_001357453.1
TMIE	NM_001370525.1 linkuse as main transcript	c.82C>T	p.Arg28Cys	missense_variant	4/5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	Appris
TMIE	ENST00000643606.3 linkuse as main transcript	c.241C>T	p.Arg81Cys	missense_variant	3/4	NM_147196.3	ENSP00000494576	P1
TMIE	ENST00000644830.1 linkuse as main transcript	c.82C>T	p.Arg28Cys	missense_variant	3/4		ENSP00000495111
TMIE	ENST00000651652.1 linkuse as main transcript	c.139C>T	p.Arg47Cys	missense_variant	2/2		ENSP00000498953

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 6

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2002

- -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12145746, 16389551, 24949729, 30303587, 26186295) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;D;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

1.9

.;L;L

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.9

.;.;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

.;.;D

Sift4G

Pathogenic

0.0

.;.;D

Polyphen

1.0

.;D;D

Vest4

0.93

MutPred

0.79

.;Loss of MoRF binding (P = 0.0526);Loss of MoRF binding (P = 0.0526);

MVP

0.94

MPC

1.1

ClinPred

1.0

GERP RS

5.6

Varity_R

0.85

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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