NM_147196.3:c.94-2_98delAGCCCAGinsC

Variant names:

• chr3-46705788-AGCCCAG-C
• rs876657371
• NM_147196.3:c.94-2_98delAGCCCAGinsC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_147196.3(TMIE):​c.94-2_98delAGCCCAGinsC​(p.Pro32fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMIE NM_147196.3 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.29
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 6

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-46705788-AGCCCAG-C is Pathogenic according to our data. Variant chr3-46705788-AGCCCAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3393.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147196.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	NM_147196.3	MANE Select	c.94-2_98delAGCCCAGinsC	p.Pro32fs	frameshift splice_acceptor splice_region intron	Exon 2 of 4	NP_671729.2	Q8NEW7
	TMIE	NM_001370524.1		c.-66-2_-62delAGCCCAGinsC		splice_region	Exon 2 of 4	NP_001357453.1	A0A2R8YDZ8
	TMIE	NM_001370525.1		c.-66-2_-62delAGCCCAGinsC		splice_region	Exon 3 of 5	NP_001357454.1	A0A2R8YDZ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000643606.3	MANE Select	c.94-2_98delAGCCCAGinsC	p.Pro32fs	frameshift splice_acceptor splice_region intron	Exon 2 of 4	ENSP00000494576.2	Q8NEW7
	TMIE	ENST00000644830.1		c.-66-2_-62delAGCCCAGinsC		splice_region	Exon 2 of 4	ENSP00000495111.1	A0A2R8YDZ8
	TMIE	ENST00000644830.1		c.-66-2_-62delAGCCCAGinsC		splice_acceptor 5_prime_UTR intron	Exon 2 of 4	ENSP00000495111.1	A0A2R8YDZ8

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive nonsyndromic hearing loss 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=14/186	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs876657371; hg19: chr3-46747278;