chr3-46709583-TAAG-T

Position:

• chr3-46709583-TAAG-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BA1

The NM_147196.3(TMIE):​c.391_393del​(p.Lys131del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42038 hom., cov: 0)
  • Exomes 𝑓: 0.55 (105822 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMIE NM_147196.3 inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.815

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]

ACMG classification

Verdict is Benign. Variant got -14 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
• BP6: Variant 3-46709583-TAAG-T is Benign according to our data. Variant chr3-46709583-TAAG-T is described in ClinVar as [Benign]. Clinvar id is 47962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-46709583-TAAG-T is described in Lovd as [Benign]. Variant chr3-46709583-TAAG-T is described in Lovd as [Likely_benign]. Variant chr3-46709583-TAAG-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMIE	NM_147196.3	c.391_393del	p.Lys131del	inframe_deletion	4/4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.232_234del	p.Lys78del	inframe_deletion	4/4		NP_001357453.1
TMIE	NM_001370525.1	c.232_234del	p.Lys78del	inframe_deletion	5/5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3	c.391_393del	p.Lys131del	inframe_deletion	4/4		NM_147196.3	ENSP00000494576	P1
TMIE	ENST00000644830.1	c.232_234del	p.Lys78del	inframe_deletion	4/4			ENSP00000495111
TMIE	ENST00000651652.1	c.*313_*315del		3_prime_UTR_variant	2/2			ENSP00000498953

Frequencies

GnomAD3 genomes AF: 0.748 AC: 112115 AN: 149792 Hom.: 42021 Cov.: 0

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.749

GnomAD3 exomes AF: 0.612 AC: 89034 AN: 145554 Hom.: 20154 AF XY: 0.604 AC XY: 47317 AN XY: 78324

Gnomad AFR exome AF: 0.707

Gnomad AMR exome AF: 0.598

Gnomad ASJ exome AF: 0.562

Gnomad EAS exome AF: 0.567

Gnomad SAS exome AF: 0.546

Gnomad FIN exome AF: 0.701

Gnomad NFE exome AF: 0.610

Gnomad OTH exome AF: 0.582

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.551 AC: 752987 AN: 1365922 Hom.: 105822 AF XY: 0.549 AC XY: 372988 AN XY: 679048

Gnomad4 AFR exome AF: 0.590

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.538

Gnomad4 EAS exome AF: 0.526

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.588

Gnomad4 NFE exome AF: 0.552

Gnomad4 OTH exome AF: 0.548

GnomAD4 genome AF: 0.748 AC: 112186 AN: 149900 Hom.: 42038 Cov.: 0 AF XY: 0.749 AC XY: 54678 AN XY: 73028

Gnomad4 AFR AF: 0.824

Gnomad4 AMR AF: 0.759

Gnomad4 ASJ AF: 0.745

Gnomad4 EAS AF: 0.653

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.740

Gnomad4 NFE AF: 0.713

Gnomad4 OTH AF: 0.749

Bravo AF: 0.766

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 08, 2012	- -

Autosomal recessive nonsyndromic hearing loss 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2017	This variant is associated with the following publications: (PMID: 27045574) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs10578999; hg19: chr3-46751073;