Genetic Variant TMIE:p.Lys130_Lys131del (chr3-46709583-TAAGAAG-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id 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 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.388_393delAAGAAG	p.Lys130_Lys131del	conservative_inframe_deletion	Exon 4 of 4	ENST00000643606.3	NP_671729.2	Q8NEW7
TMIE	NM_001370524.1 link	c.229_234delAAGAAG	p.Lys77_Lys78del	conservative_inframe_deletion	Exon 4 of 4		NP_001357453.1
TMIE	NM_001370525.1 link	c.229_234delAAGAAG	p.Lys77_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.388_393delAAGAAG	p.Lys130_Lys131del	conservative_inframe_deletion	Exon 4 of 4	NM_147196.3	ENSP00000494576.2	Q8NEW7
TMIE	ENST00000644830.1 link	c.229_234delAAGAAG	p.Lys77_Lys78del	conservative_inframe_deletion	Exon 4 of 4		ENSP00000495111.1	A0A2R8YDZ8
TMIE	ENST00000651652.1 link	c.310_315delAAGAAG		3_prime_UTR_variant	Exon 2 of 2		ENSP00000498953.1	A0A494C1A3

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

GnomAD3 exomes

AF:

0.00926

AC:

1348

AN:

145554

Hom.:

AF XY:

0.00915

AC XY:

717

AN XY:

78324

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 SAS exome

AF:

0.00888

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

Gnomad4 AFR exome

AF:

0.0273

Gnomad4 AMR exome

AF:

0.0185

Gnomad4 ASJ exome

AF:

0.0192

Gnomad4 EAS exome

AF:

0.0130

Gnomad4 SAS exome

AF:

0.0139

Gnomad4 FIN exome

AF:

0.0157

Gnomad4 NFE exome

AF:

0.0187

Gnomad4 OTH exome

AF:

0.0199

GnomAD4 genome

AF:

0.00159

AC:

237

AN:

149158

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

117

AN XY:

72620

show subpopulations

Gnomad4 AFR

AF:

0.00162

Gnomad4 AMR

AF:

0.00107

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000989

Gnomad4 SAS

AF:

0.000636

Gnomad4 FIN

AF:

0.00234

Gnomad4 NFE

AF:

0.00180

Gnomad4 OTH

AF:

0.00145

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 v4.3

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