16-19460310-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001261841.2(TMC5):​c.1124C>T​(p.Thr375Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMC5
NM_001261841.2 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09
Variant links:
Genes affected
TMC5 (HGNC:22999): (transmembrane channel like 5) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31708956).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMC5NM_001261841.2 linkc.1124C>T p.Thr375Ile missense_variant Exon 6 of 22 ENST00000542583.7 NP_001248770.1 Q6UXY8-1B7Z946

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMC5ENST00000542583.7 linkc.1124C>T p.Thr375Ile missense_variant Exon 6 of 22 2 NM_001261841.2 ENSP00000446274.2 Q6UXY8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461288
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727014
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000224
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 13, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1124C>T (p.T375I) alteration is located in exon 6 (coding exon 4) of the TMC5 gene. This alteration results from a C to T substitution at nucleotide position 1124, causing the threonine (T) at amino acid position 375 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Benign
-0.052
T
BayesDel_noAF
Benign
-0.31
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.075
.;.;T;T;.;.;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.87
D;D;D;.;D;D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.32
T;T;T;T;T;T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Uncertain
2.9
.;M;M;M;.;.;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.4
D;D;D;D;D;D;D
REVEL
Benign
0.14
Sift
Uncertain
0.0070
D;D;D;D;D;D;D
Sift4G
Uncertain
0.0070
D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;.;.
Vest4
0.31
MutPred
0.28
Loss of phosphorylation at T375 (P = 0.0292);Loss of phosphorylation at T375 (P = 0.0292);Loss of phosphorylation at T375 (P = 0.0292);Loss of phosphorylation at T375 (P = 0.0292);.;.;.;
MVP
0.52
MPC
0.62
ClinPred
0.97
D
GERP RS
3.3
Varity_R
0.21
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1422996241; hg19: chr16-19471632; API