3-46709165-G-T

Position:

• chr3-46709165-G-T

Variant summary

Our verdict is Pathogenic. Variant got 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 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

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 Pathogenic. Variant got 10 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
• 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 Lovd as [Pathogenic].
• 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 id is 47958.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-46709165-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMIE	NM_147196.3	c.251G>T	p.Arg84Leu	missense_variant	3/4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.92G>T	p.Arg31Leu	missense_variant	3/4		NP_001357453.1
TMIE	NM_001370525.1	c.92G>T	p.Arg31Leu	missense_variant	4/5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3	c.251G>T	p.Arg84Leu	missense_variant	3/4		NM_147196.3	ENSP00000494576	P1
TMIE	ENST00000644830.1	c.92G>T	p.Arg31Leu	missense_variant	3/4			ENSP00000495111
TMIE	ENST00000651652.1	c.149G>T	p.Arg50Leu	missense_variant	2/2			ENSP00000498953

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 18, 2013

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 v4.3

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;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.9	.;L;L
MutationTaster	Benign	1.0	D
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;D
Vest4		0.95
MutPred		0.46		.;Gain of relative solvent accessibility (P = 0.0166);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517866; hg19: chr3-46750655;