NM_147196.3:c.388_393delAAGAAG

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_393delAAGAAG(p.Lys130_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 0.016 in 1,088,952 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K130K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 0)

Exomes 𝑓: 0.018 ( 1 hom. )

Consequence

TMIE
NM_147196.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.82

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-TAAGAAG-T is Benign according to our data. Variant chr3-46709583-TAAGAAG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00159 (237/149158) while in subpopulation NFE AF = 0.0018 (121/67160). AF 95% confidence interval is 0.00154. There are 1 homozygotes in GnomAd4. There are 117 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_393delAAGAAG	p.Lys130_Lys131del	conservative_inframe_deletion	Exon 4 of 4	NP_671729.2
TMIE	NM_001370524.1		c.229_234delAAGAAG	p.Lys77_Lys78del	conservative_inframe_deletion	Exon 4 of 4	NP_001357453.1
TMIE	NM_001370525.1		c.229_234delAAGAAG	p.Lys77_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.388_393delAAGAAG	p.Lys130_Lys131del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000494576.2
TMIE	ENST00000644830.1		c.229_234delAAGAAG	p.Lys77_Lys78del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000495111.1
TMIE	ENST00000651652.1		c.310_315delAAGAAG		3_prime_UTR	Exon 2 of 2	ENSP00000498953.1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

235

AN:

149048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00158

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000986

Gnomad SAS

AF:

0.000636

Gnomad FIN

AF:

0.00234

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00180

Gnomad OTH

AF:

0.00146

GnomAD2 exomes

AF:

0.00926

AC:

1348

AN:

145554

AF XY:

0.00915

show subpopulations

Gnomad AFR exome

AF:

0.00882

Gnomad AMR exome

AF:

0.0129

Gnomad ASJ exome

AF:

0.00612

Gnomad EAS exome

AF:

0.00622

Gnomad FIN exome

AF:

0.00582

Gnomad NFE exome

AF:

0.00986

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.0183

AC:

17216

AN:

939794

Hom.:

AF XY:

0.0177

AC XY:

8215

AN XY:

463448

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0273

AC:

485

AN:

17784

American (AMR)

AF:

0.0185

AC:

415

AN:

22456

Ashkenazi Jewish (ASJ)

AF:

0.0192

AC:

277

AN:

14396

East Asian (EAS)

AF:

0.0130

AC:

375

AN:

28862

South Asian (SAS)

AF:

0.0139

AC:

670

AN:

48354

European-Finnish (FIN)

AF:

0.0157

AC:

540

AN:

34330

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

4316

European-Non Finnish (NFE)

AF:

0.0187

AC:

13633

AN:

730730

Other (OTH)

AF:

0.0199

AC:

767

AN:

38566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.268

Heterozygous variant carriers

2733

5467

8200

10934

13667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

572

1144

1716

2288

2860

<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:

0.00159

AC:

237

AN:

149158

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

117

AN XY:

72620

show subpopulations

African (AFR)

AF:

0.00162

AC:

AN:

40718

American (AMR)

AF:

0.00107

AC:

AN:

14982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.000989

AC:

AN:

5058

South Asian (SAS)

AF:

0.000636

AC:

AN:

4716

European-Finnish (FIN)

AF:

0.00234

AC:

AN:

9828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00180

AC:

121

AN:

67160

Other (OTH)

AF:

0.00145

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.161

Hom.:

1309

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 21, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=189/11

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