3-46709583-TAAGAAGAAGAAGAAG-TAAGAAGAAGAAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_147196.3(TMIE):c.391_393delAAG(p.Lys131del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K131K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.75 ( 42038 hom., cov: 0)

Exomes 𝑓: 0.55 ( 105822 hom. )

Failed GnomAD Quality Control

Consequence

TMIE
NM_147196.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.815

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: Benign. The variant received -16 ACMG points.

BP6

Variant 3-46709583-TAAG-T is Benign according to our data. Variant chr3-46709583-TAAG-T is described in ClinVar as Benign. ClinVar VariationId is 47962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

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.391_393delAAG	p.Lys131del	conservative_inframe_deletion	Exon 4 of 4	NP_671729.2
TMIE	NM_001370524.1		c.232_234delAAG	p.Lys78del	conservative_inframe_deletion	Exon 4 of 4	NP_001357453.1
TMIE	NM_001370525.1		c.232_234delAAG	p.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.391_393delAAG	p.Lys131del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000494576.2
TMIE	ENST00000644830.1		c.232_234delAAG	p.Lys78del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000495111.1
TMIE	ENST00000651652.1		c.313_315delAAG		3_prime_UTR	Exon 2 of 2	ENSP00000498953.1

Frequencies

GnomAD3 genomes

AF:

0.748

AC:

112115

AN:

149792

Hom.:

42021

Cov.:

show subpopulations

Gnomad AFR

AF:

0.824

Gnomad AMI

AF:

0.603

Gnomad AMR

AF:

0.759

Gnomad ASJ

AF:

0.745

Gnomad EAS

AF:

0.654

Gnomad SAS

AF:

0.728

Gnomad FIN

AF:

0.740

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.713

Gnomad OTH

AF:

0.749

GnomAD2 exomes

AF:

0.612

AC:

89034

AN:

145554

AF XY:

0.604

show subpopulations

Gnomad AFR exome

AF:

0.707

Gnomad AMR exome

AF:

0.598

Gnomad ASJ exome

AF:

0.562

Gnomad EAS exome

AF:

0.567

Gnomad FIN exome

AF:

0.701

Gnomad NFE exome

AF:

0.610

Gnomad OTH exome

AF:

0.582

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.551

AC:

752987

AN:

1365922

Hom.:

105822

AF XY:

0.549

AC XY:

372988

AN XY:

679048

show subpopulations

African (AFR)

AF:

0.590

AC:

18586

AN:

31520

American (AMR)

AF:

0.555

AC:

23604

AN:

42550

Ashkenazi Jewish (ASJ)

AF:

0.538

AC:

13215

AN:

24552

East Asian (EAS)

AF:

0.526

AC:

18765

AN:

35672

South Asian (SAS)

AF:

0.522

AC:

41996

AN:

80480

European-Finnish (FIN)

AF:

0.588

AC:

29467

AN:

50096

Middle Eastern (MID)

AF:

0.575

AC:

3133

AN:

5448

European-Non Finnish (NFE)

AF:

0.552

AC:

573332

AN:

1039218

Other (OTH)

AF:

0.548

AC:

30889

AN:

56386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.655

Heterozygous variant carriers

26389

52778

79166

105555

131944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18928

37856

56784

75712

94640

<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:

0.748

AC:

112186

AN:

149900

Hom.:

42038

Cov.:

AF XY:

0.749

AC XY:

54678

AN XY:

73028

show subpopulations

African (AFR)

AF:

0.824

AC:

33587

AN:

40780

American (AMR)

AF:

0.759

AC:

11421

AN:

15046

Ashkenazi Jewish (ASJ)

AF:

0.745

AC:

2572

AN:

3452

East Asian (EAS)

AF:

0.653

AC:

3304

AN:

5056

South Asian (SAS)

AF:

0.727

AC:

3429

AN:

4714

European-Finnish (FIN)

AF:

0.740

AC:

7517

AN:

10162

Middle Eastern (MID)

AF:

0.741

AC:

215

AN:

290

European-Non Finnish (NFE)

AF:

0.713

AC:

48032

AN:

67408

Other (OTH)

AF:

0.749

AC:

1565

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1350

2700

4050

5400

6750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.549

Hom.:

1309

Bravo

AF:

0.766

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 10, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 08, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal recessive nonsyndromic hearing loss 6

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

May 17, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27045574)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.81

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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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