3-46709165-G-T

Variant names:

• chr3-46709165-G-T
• rs397517866
• NM_147196.3:c.251G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_147196.3(TMIE):​c.251G>T​(p.Arg84Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R84W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMIE NM_147196.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.38
• Publications: 2 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_147196.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-46709164-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 3-46709165-G-T is Pathogenic according to our data. Variant chr3-46709165-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 47958.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	NM_147196.3	MANE Select	c.251G>T	p.Arg84Leu	missense	Exon 3 of 4	NP_671729.2
	TMIE	NM_001370524.1		c.92G>T	p.Arg31Leu	missense	Exon 3 of 4	NP_001357453.1
	TMIE	NM_001370525.1		c.92G>T	p.Arg31Leu	missense	Exon 4 of 5	NP_001357454.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMIE	ENST00000643606.3	MANE Select	c.251G>T	p.Arg84Leu	missense	Exon 3 of 4	ENSP00000494576.2
	TMIE	ENST00000644830.1		c.92G>T	p.Arg31Leu	missense	Exon 3 of 4	ENSP00000495111.1
	TMIE	ENST00000651652.1		c.149G>T	p.Arg50Leu	missense	Exon 2 of 2	ENSP00000498953.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Jan 18, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg84Leu variant in TMIE has not been reported in the literature nor previou sly identified by our laboratory. However, another pathogenic variant affecting the same amino acid (Arg84Trp) has been reported as a founder mutation in the Tu rkish population (Sirmaci 2009). The Arg84Leu variant has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/). Computational analyses (biochemical amino acid propertie s, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg84Leu varia nt may impact the protein, though this information is not predictive enough to d etermine pathogenicity. In summary, the clinical significance of this variant ca nnot be determined with certainty; however, its occurrence at the same amino aci d position of another known pathogenic mutation and the presence of a second var iant in trans in this individual's son support a likely pathogenic role.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.46		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.83
gMVP		0.93
Mutation Taster		=80/20	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397517866; hg19: chr3-46750655;