3-46709583-TAAGAAGAAGAAGAAG-TAAGAAGAAGAAGAAGAAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_147196.3(TMIE):c.391_393dupAAG(p.Lys131dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.010 ( 26 hom., cov: 0)

Exomes 𝑓: 0.0024 ( 0 hom. )

Consequence

TMIE
NM_147196.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.773

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 -9 ACMG points.

BP6

Variant 3-46709583-T-TAAG is Benign according to our data. Variant chr3-46709583-T-TAAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179307.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1506/150044) while in subpopulation AFR AF = 0.0293 (1195/40790). AF 95% confidence interval is 0.0279. There are 26 homozygotes in GnomAd4. There are 680 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

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_393dupAAG	p.Lys131dup	conservative_inframe_insertion	Exon 4 of 4	NP_671729.2
TMIE	NM_001370524.1		c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	Exon 4 of 4	NP_001357453.1
TMIE	NM_001370525.1		c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	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_393dupAAG	p.Lys131dup	conservative_inframe_insertion	Exon 4 of 4	ENSP00000494576.2
TMIE	ENST00000644830.1		c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	Exon 4 of 4	ENSP00000495111.1
TMIE	ENST00000651652.1		c.313_315dupAAG		3_prime_UTR	Exon 2 of 2	ENSP00000498953.1

Frequencies

GnomAD3 genomes

AF:

0.00999

AC:

1498

AN:

149934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0292

Gnomad AMI

AF:

0.0698

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00637

Gnomad EAS

AF:

0.000591

Gnomad SAS

AF:

0.00381

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.00629

GnomAD2 exomes

AF:

0.00599

AC:

872

AN:

145554

AF XY:

0.00539

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.00567

Gnomad ASJ exome

AF:

0.00801

Gnomad EAS exome

AF:

0.000711

Gnomad FIN exome

AF:

0.000129

Gnomad NFE exome

AF:

0.00263

Gnomad OTH exome

AF:

0.00483

GnomAD4 exome

AF:

0.00239

AC:

3353

AN:

1402534

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

1567

AN XY:

698872

show subpopulations

African (AFR)

AF:

0.0326

AC:

1037

AN:

31782

American (AMR)

AF:

0.00309

AC:

135

AN:

43630

Ashkenazi Jewish (ASJ)

AF:

0.00450

AC:

114

AN:

25346

East Asian (EAS)

AF:

0.000438

AC:

AN:

38818

South Asian (SAS)

AF:

0.00257

AC:

218

AN:

84782

European-Finnish (FIN)

AF:

0.000174

AC:

AN:

51750

Middle Eastern (MID)

AF:

0.00320

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.00151

AC:

1600

AN:

1062698

Other (OTH)

AF:

0.00353

AC:

205

AN:

58100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

205

410

614

819

1024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

152

228

304

380

<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:

0.0100

AC:

1506

AN:

150044

Hom.:

Cov.:

AF XY:

0.00930

AC XY:

680

AN XY:

73120

show subpopulations

African (AFR)

AF:

0.0293

AC:

1195

AN:

40790

American (AMR)

AF:

0.00425

AC:

AN:

15060

Ashkenazi Jewish (ASJ)

AF:

0.00637

AC:

AN:

3452

East Asian (EAS)

AF:

0.000592

AC:

AN:

5064

South Asian (SAS)

AF:

0.00360

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:

0.00190

AC:

128

AN:

67484

Other (OTH)

AF:

0.00670

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

134

201

268

335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00189

Hom.:

1309

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lys131_Asp132insLys in Exon 4 of TMIE: This variant is not expected to have clin ical significance because it results in the an insertion of a Lys residue in a p oly-Lysine tract.

not provided

Benign:2

Sep 13, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hearing loss, autosomal recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.77

Mutation Taster

=89/11

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