rs397517372
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001256317.3(TMPRSS3):c.257T>A(p.Ile86Asn) 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 (★). Synonymous variant affecting the same amino acid position (i.e. I86I) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
TMPRSS3
NM_001256317.3 missense
NM_001256317.3 missense
Scores
7
5
2
Clinical Significance
Conservation
PhyloP100: 7.29
Genes affected
TMPRSS3 (HGNC:11877): (transmembrane serine protease 3) This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified by its association with both congenital and childhood onset autosomal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and maintenance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.257T>A | p.Ile86Asn | missense_variant | 4/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.257T>A | p.Ile86Asn | missense_variant | 4/13 | ||
TMPRSS3 | NM_032405.2 | c.257T>A | p.Ile86Asn | missense_variant | 4/9 | ||
TMPRSS3 | NM_032404.3 | c.-125T>A | 5_prime_UTR_variant | 1/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.257T>A | p.Ile86Asn | missense_variant | 4/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 17, 2011 | The Ile86Asn variant in TMPRSS3 has not been reported in the literature nor previously identified by our laboratory. This residue is conserved across most species, except in rhesus monkey. Computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the Ile86Asn variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. It should be noted that this lab has only sequenced and CDH23 and TMPRSS3 in 24 African American or Black probands and no African American or Black healthy controls. Future analysis could reveal that the Ile86Asn variant is common in this population and therefore unlikely to be pathogenic. In summary, the clinical significance of this variant cannot be determined at this time. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;.;H
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Benign
T
Polyphen
D;D;D;.;D
Vest4
0.81, 0.80, 0.81, 0.87
MutPred
Loss of MoRF binding (P = 0.1417);Loss of MoRF binding (P = 0.1417);Loss of MoRF binding (P = 0.1417);.;Loss of MoRF binding (P = 0.1417);
MVP
0.99
MPC
0.71
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at