NM_147196.3:c.385_393delAAGAAGAAG

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP6BS1

The NM_147196.3(TMIE):c.385_393delAAGAAGAAG(p.Lys129_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 0.000467 in 1,552,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

TMIE
NM_147196.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 2.54

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a chain Transmembrane inner ear expressed protein (size 128) in uniprot entity TMIE_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_147196.3

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 3-46709583-TAAGAAGAAG-T is Benign according to our data. Variant chr3-46709583-TAAGAAGAAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227101.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=2}. Variant chr3-46709583-TAAGAAGAAG-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000373 (56/150058) while in subpopulation SAS AF= 0.00403 (19/4720). AF 95% confidence interval is 0.00264. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3 link	c.385_393delAAGAAGAAG	p.Lys129_Lys131del	conservative_inframe_deletion	Exon 4 of 4	ENST00000643606.3	NP_671729.2	Q8NEW7
TMIE	NM_001370524.1 link	c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 4 of 4		NP_001357453.1
TMIE	NM_001370525.1 link	c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 5 of 5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	ENST00000643606.3 link	c.385_393delAAGAAGAAG	p.Lys129_Lys131del	conservative_inframe_deletion	Exon 4 of 4	NM_147196.3	ENSP00000494576.2	Q8NEW7
TMIE	ENST00000644830.1 link	c.226_234delAAGAAGAAG	p.Lys76_Lys78del	conservative_inframe_deletion	Exon 4 of 4		ENSP00000495111.1	A0A2R8YDZ8
TMIE	ENST00000651652.1 link	c.307_315delAAGAAGAAG		3_prime_UTR_variant	Exon 2 of 2		ENSP00000498953.1	A0A494C1A3

Frequencies

GnomAD3 genomes

AF:

0.000373

AC:

AN:

149948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000399

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00402

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000267

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.00129

AC:

188

AN:

145554

Hom.:

AF XY:

0.00175

AC XY:

137

AN XY:

78324

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.000667

Gnomad ASJ exome

AF:

0.000633

Gnomad EAS exome

AF:

0.000534

Gnomad SAS exome

AF:

0.00674

Gnomad FIN exome

AF:

0.000129

Gnomad NFE exome

AF:

0.000769

Gnomad OTH exome

AF:

0.00211

GnomAD4 exome

AF:

0.000477

AC:

669

AN:

1402350

Hom.:

AF XY:

0.000591

AC XY:

413

AN XY:

698780

show subpopulations

Gnomad4 AFR exome

AF:

0.000126

Gnomad4 AMR exome

AF:

0.000573

Gnomad4 ASJ exome

AF:

0.000276

Gnomad4 EAS exome

AF:

0.000232

Gnomad4 SAS exome

AF:

0.00368

Gnomad4 FIN exome

AF:

0.000155

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.000843

GnomAD4 genome

AF:

0.000373

AC:

AN:

150058

Hom.:

Cov.:

AF XY:

0.000383

AC XY:

AN XY:

73126

show subpopulations

Gnomad4 AFR

AF:

0.000245

Gnomad4 AMR

AF:

0.000398

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00403

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000267

Gnomad4 OTH

AF:

0.000478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Sep 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Feb 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Lys129_Lys131del in Exon 4 of TMIE: This variant is not expected to have clini cal significance because it results in an in-frame deletion of 3 lysine (Lys) re sidues in a nonconserved lysine tract and does not alter the amino acid reading frame. It has been identified in 0.4% (62/15930) of South Asian chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). -

TMIE-related disorder

Benign:1

Nov 14, 2019

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 v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over