3-46709583-TAAGAAGAAGAAGAAG-TAAGAAG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_147196.3(TMIE):c.385_393delAAGAAGAAG(p.Lys129_Lys131del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000467 in 1,552,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

TMIE
NM_147196.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.54

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 6
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMIE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 3-46709583-TAAGAAGAAG-T is Benign according to our data. Variant chr3-46709583-TAAGAAGAAG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227101.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000373 (56/150058) while in subpopulation SAS AF = 0.00403 (19/4720). AF 95% confidence interval is 0.00264. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147196.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMIE	NM_147196.3	MANE Select	c.385_393delAAGAAGAAG	p.Lys129_Lys131del	conservative_inframe_deletion	Exon 4 of 4	NP_671729.2
TMIE	NM_001370524.1		c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 4 of 4	NP_001357453.1
TMIE	NM_001370525.1		c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 5 of 5	NP_001357454.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMIE	ENST00000643606.3	MANE Select	c.385_393delAAGAAGAAG	p.Lys129_Lys131del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000494576.2
TMIE	ENST00000644830.1		c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000495111.1
TMIE	ENST00000651652.1		c.307_315delAAGAAGAAG		3_prime_UTR	Exon 2 of 2	ENSP00000498953.1

Frequencies

GnomAD3 genomes

AF:

0.000373

AC:

AN:

149948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000399

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00402

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000267

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.00129

AC:

188

AN:

145554

AF XY:

0.00175

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.000667

Gnomad ASJ exome

AF:

0.000633

Gnomad EAS exome

AF:

0.000534

Gnomad FIN exome

AF:

0.000129

Gnomad NFE exome

AF:

0.000769

Gnomad OTH exome

AF:

0.00211

GnomAD4 exome

AF:

0.000477

AC:

669

AN:

1402350

Hom.:

AF XY:

0.000591

AC XY:

413

AN XY:

698780

show subpopulations

African (AFR)

AF:

0.000126

AC:

AN:

31782

American (AMR)

AF:

0.000573

AC:

AN:

43626

Ashkenazi Jewish (ASJ)

AF:

0.000276

AC:

AN:

25342

East Asian (EAS)

AF:

0.000232

AC:

AN:

38816

South Asian (SAS)

AF:

0.00368

AC:

312

AN:

84778

European-Finnish (FIN)

AF:

0.000155

AC:

AN:

51738

Middle Eastern (MID)

AF:

0.00213

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.000229

AC:

243

AN:

1062548

Other (OTH)

AF:

0.000843

AC:

AN:

58094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000373

AC:

AN:

150058

Hom.:

Cov.:

AF XY:

0.000383

AC XY:

AN XY:

73126

show subpopulations

African (AFR)

AF:

0.000245

AC:

AN:

40804

American (AMR)

AF:

0.000398

AC:

AN:

15060

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3452

East Asian (EAS)

AF:

0.000197

AC:

AN:

5064

South Asian (SAS)

AF:

0.00403

AC:

AN:

4720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000267

AC:

AN:

67484

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000771

Hom.:

1309

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Sep 01, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 17, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Feb 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Lys129_Lys131del in Exon 4 of TMIE: This variant is not expected to have clini cal significance because it results in an in-frame deletion of 3 lysine (Lys) re sidues in a nonconserved lysine tract and does not alter the amino acid reading frame. It has been identified in 0.4% (62/15930) of South Asian chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org).

TMIE-related disorder

Benign:1

Nov 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=183/17

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over