3-46709583-T-TAAG

Variant names:

• chr3-46709583-T-TAAG
• rs10578999
• NM_147196.3:c.391_393dupAAG

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP6 BS1 BS2

The NM_147196.3(TMIE):​c.391_393dupAAG​(p.Lys131dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (0 hom.)
• Consequence: TMIE NM_147196.3 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.773

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 -7 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-T-TAAG is Benign according to our data. Variant chr3-46709583-T-TAAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179307.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1506/150044) while in subpopulation AFR AF= 0.0293 (1195/40790). AF 95% confidence interval is 0.0279. There are 26 homozygotes in gnomad4. There are 680 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3	c.391_393dupAAG	p.Lys131dup	conservative_inframe_insertion	Exon 4 of 4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	Exon 4 of 4		NP_001357453.1
TMIE	NM_001370525.1	c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	Exon 5 of 5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3	c.391_393dupAAG	p.Lys131dup	conservative_inframe_insertion	Exon 4 of 4		NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1	c.232_234dupAAG	p.Lys78dup	conservative_inframe_insertion	Exon 4 of 4			ENSP00000495111.1
TMIE	ENST00000651652.1	c.*313_*315dupAAG		3_prime_UTR_variant	Exon 2 of 2			ENSP00000498953.1

Frequencies

GnomAD3 genomes AF: 0.00999 AC: 1498 AN: 149934 Hom.: 25 Cov.: 0

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.0698

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00637

Gnomad EAS AF: 0.000591

Gnomad SAS AF: 0.00381

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00629

GnomAD3 exomes AF: 0.00599 AC: 872 AN: 145554 Hom.: 1 AF XY: 0.00539 AC XY: 422 AN XY: 78324

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.00801

Gnomad EAS exome AF: 0.000711

Gnomad SAS exome AF: 0.00519

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00483

GnomAD4 exome AF: 0.00239 AC: 3353 AN: 1402534 Hom.: 0 Cov.: 0 AF XY: 0.00224 AC XY: 1567 AN XY: 698872

Gnomad4 AFR exome AF: 0.0326

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00450

Gnomad4 EAS exome AF: 0.000438

Gnomad4 SAS exome AF: 0.00257

Gnomad4 FIN exome AF: 0.000174

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.0100 AC: 1506 AN: 150044 Hom.: 26 Cov.: 0 AF XY: 0.00930 AC XY: 680 AN XY: 73120

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00637

Gnomad4 EAS AF: 0.000592

Gnomad4 SAS AF: 0.00360

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00670

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Oct 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lys131_Asp132insLys in Exon 4 of TMIE: This variant is not expected to have clin ical significance because it results in the an insertion of a Lys residue in a p oly-Lysine tract. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing loss, autosomal recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;