Genetic Variant TMIE:p.Lys128_Lys131del (chr3-46709583-TAAGAAGAAGAAG-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_147196.3(TMIE):c.382_393delAAGAAGAAGAAG(p.Lys128_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 0.0000116 in 1,552,536 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

TMIE
NM_147196.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMIE	NM_147196.3 link	c.382_393delAAGAAGAAGAAG	p.Lys128_Lys131del	conservative_inframe_deletion	Exon 4 of 4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1 link	c.223_234delAAGAAGAAGAAG	p.Lys75_Lys78del	conservative_inframe_deletion	Exon 4 of 4		NP_001357453.1
TMIE	NM_001370525.1 link	c.223_234delAAGAAGAAGAAG	p.Lys75_Lys78del	conservative_inframe_deletion	Exon 5 of 5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMIE	ENST00000643606.3 link	c.382_393delAAGAAGAAGAAG	p.Lys128_Lys131del	conservative_inframe_deletion	Exon 4 of 4	NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1 link	c.223_234delAAGAAGAAGAAG	p.Lys75_Lys78del	conservative_inframe_deletion	Exon 4 of 4		ENSP00000495111.1
TMIE	ENST00000651652.1 link	c.304_315delAAGAAGAAGAAG		3_prime_UTR_variant	Exon 2 of 2		ENSP00000498953.1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

149948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1402588

Hom.:

AF XY:

0.00000858

AC XY:

AN XY:

698902

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31790

American (AMR)

AF:

0.00

AC:

AN:

43630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25346

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38820

South Asian (SAS)

AF:

0.00

AC:

AN:

84780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.0000141

AC:

AN:

1062742

Other (OTH)

AF:

0.00

AC:

AN:

58102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.0000133

AC:

AN:

149948

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40688

American (AMR)

AF:

0.00

AC:

AN:

15042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000296

AC:

AN:

67492

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1309

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=176/24

polymorphism

(source)

Splicing

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

Publications

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3-46709583-TAAGAAGAAGAAGAAG-TAAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over