NM_147196.3:c.247C>T

Variant names:

• chr3-46709161-C-T
• rs876658019
• NM_147196.3:c.247C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_147196.3(TMIE):​c.247C>T​(p.Pro83Ser) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMIE NM_147196.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 Uncertain_significance. Variant got 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMIE	NM_147196.3	c.247C>T	p.Pro83Ser	missense_variant	Exon 3 of 4	ENST00000643606.3	NP_671729.2
TMIE	NM_001370524.1	c.88C>T	p.Pro30Ser	missense_variant	Exon 3 of 4		NP_001357453.1
TMIE	NM_001370525.1	c.88C>T	p.Pro30Ser	missense_variant	Exon 4 of 5		NP_001357454.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMIE	ENST00000643606.3	c.247C>T	p.Pro83Ser	missense_variant	Exon 3 of 4		NM_147196.3	ENSP00000494576.2
TMIE	ENST00000644830.1	c.88C>T	p.Pro30Ser	missense_variant	Exon 3 of 4			ENSP00000495111.1
TMIE	ENST00000651652.1	c.145C>T	p.Pro49Ser	missense_variant	Exon 2 of 2			ENSP00000498953.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro83Ser variant in TMIE has not been previously reported in individuals w ith hearing loss or in large population studies. Computational prediction tools and conservation analyses suggest that the p.Pro83Ser variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, the clinical significance of the p.Pro83Ser variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;D;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.9	.;L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.6	.;.;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;.;D
Sift4G	Pathogenic	0.0	.;.;D
Polyphen		1.0	.;D;D
Vest4		0.89
MutPred		0.34		.;Gain of MoRF binding (P = 0.0449);Gain of MoRF binding (P = 0.0449);
MVP		0.87
MPC		0.88
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs876658019; hg19: chr3-46750651;