rs876658019

chr3-46709161-C-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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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/exons	MANE	UniProt
TMIE	NM_147196.3	c.247C>T	p.Pro83Ser	missense_variant	3/4	ENST00000643606.3
TMIE	NM_001370524.1	c.88C>T	p.Pro30Ser	missense_variant	3/4
TMIE	NM_001370525.1	c.88C>T	p.Pro30Ser	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMIE	ENST00000643606.3	c.247C>T	p.Pro83Ser	missense_variant	3/4		NM_147196.3	P1
TMIE	ENST00000644830.1	c.88C>T	p.Pro30Ser	missense_variant	3/4
TMIE	ENST00000651652.1	c.145C>T	p.Pro49Ser	missense_variant	2/2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 29, 2015

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
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
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
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;