3-46709583-TAAGAAGAAGAAGAAG-TAAGAAGAAGAAGAAGAAGAAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS1

The NM_147196.3(TMIE):c.388_393dupAAGAAG(p.Lys130_Lys131dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TMIE
NM_147196.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

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 -12 ACMG points.

BP6

Variant 3-46709583-T-TAAGAAG is Benign according to our data. Variant chr3-46709583-T-TAAGAAG is described in ClinVar as Likely_benign. ClinVar VariationId is 515000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000793 (119/150058) while in subpopulation AFR AF = 0.0027 (110/40804). AF 95% confidence interval is 0.00229. There are 0 homozygotes in GnomAd4. There are 59 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.388_393dupAAGAAG	p.Lys130_Lys131dup	conservative_inframe_insertion	Exon 4 of 4	NP_671729.2
TMIE	NM_001370524.1		c.229_234dupAAGAAG	p.Lys77_Lys78dup	conservative_inframe_insertion	Exon 4 of 4	NP_001357453.1
TMIE	NM_001370525.1		c.229_234dupAAGAAG	p.Lys77_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.388_393dupAAGAAG	p.Lys130_Lys131dup	conservative_inframe_insertion	Exon 4 of 4	ENSP00000494576.2
TMIE	ENST00000644830.1		c.229_234dupAAGAAG	p.Lys77_Lys78dup	conservative_inframe_insertion	Exon 4 of 4	ENSP00000495111.1
TMIE	ENST00000651652.1		c.310_315dupAAGAAG		3_prime_UTR	Exon 2 of 2	ENSP00000498953.1

Frequencies

GnomAD3 genomes

AF:

0.000780

AC:

117

AN:

149948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000465

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:

0.0000148

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000405

AC:

AN:

145554

AF XY:

0.000447

show subpopulations

Gnomad AFR exome

AF:

0.00577

Gnomad AMR exome

AF:

0.000200

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000889

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000559

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

173

AN:

1402588

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

698900

show subpopulations

African (AFR)

AF:

0.00349

AC:

111

AN:

31788

American (AMR)

AF:

0.0000917

AC:

AN:

43630

Ashkenazi Jewish (ASJ)

AF:

0.0000395

AC:

AN:

25346

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38820

South Asian (SAS)

AF:

0.0000236

AC:

AN:

84782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.0000395

AC:

AN:

1062742

Other (OTH)

AF:

0.000207

AC:

AN:

58102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

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:

0.000793

AC:

119

AN:

150058

Hom.:

Cov.:

AF XY:

0.000807

AC XY:

AN XY:

73126

show subpopulations

African (AFR)

AF:

0.00270

AC:

110

AN:

40804

American (AMR)

AF:

0.000465

AC:

AN:

15060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.00

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:

0.0000148

AC:

AN:

67484

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0000701

Hom.:

1309

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 25, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMIE-related disorder

Benign:1

Apr 29, 2022

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

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