Variant chr3-46705816-G-GCCGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_147196.3(TMIE):c.122_125dupCGCC(p.Pro43fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TMIE
NM_147196.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.03

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-46705816-G-GCCGC is Pathogenic according to our data. Variant chr3-46705816-G-GCCGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 984396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMIE	NM_147196.3 linkuse as main transcript	c.122_125dupCGCC	p.Pro43fs	frameshift_variant	2/4	ENST00000643606.3	NP_671729.2	Q8NEW7
TMIE	NM_001370524.1 linkuse as main transcript	c.-38_-35dupCGCC		5_prime_UTR_variant	2/4		NP_001357453.1
TMIE	NM_001370525.1 linkuse as main transcript	c.-38_-35dupCGCC		5_prime_UTR_variant	3/5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMIE	ENST00000643606.3 linkuse as main transcript	c.122_125dupCGCC	p.Pro43fs	frameshift_variant	2/4	NM_147196.3	ENSP00000494576.2	Q8NEW7
TMIE	ENST00000651652.1 linkuse as main transcript	c.20_23dupCGCC	p.Pro9fs	frameshift_variant	1/2		ENSP00000498953.1	A0A494C1A3
TMIE	ENST00000644830 linkuse as main transcript	c.-38_-35dupCGCC		5_prime_UTR_variant	2/4		ENSP00000495111.1	A0A2R8YDZ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249452

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sensorineural hearing loss disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences

Sep 30, 2020

- -

Autosomal recessive nonsyndromic hearing loss 6

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Mar 01, 2023

The frameshift variant c.122_125dup (p.Pro43AlafsTer73) in the TMIE gene has been reported previously in heterozygous and homozygous state in a family affected with Autosomal recessive non-syndromic deafness (Rayat et al., 2022). This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and novel (not in any individuals) in 1000 Genomes. It is submitted to ClinVar as Pathogenic. However, study on multiple affected individuals and the functional impact of the variant is not available. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -

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

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