chr16-19472148-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001261841.2(TMC5):​c.1843C>T​(p.Arg615Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

TMC5
NM_001261841.2 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.11
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25340834).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMC5NM_001261841.2 linkc.1843C>T p.Arg615Cys missense_variant Exon 11 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.1843C>T p.Arg615Cys missense_variant Exon 11 of 22 2 NM_001261841.2 ENSP00000446274.2 Q6UXY8-1

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251480
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000103
AC:
150
AN:
1461868
Hom.:
0
Cov.:
31
AF XY:
0.0000894
AC XY:
65
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000114
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000172
Hom.:
0
Bravo
AF:
0.0000945
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1843C>T (p.R615C) alteration is located in exon 11 (coding exon 9) of the TMC5 gene. This alteration results from a C to T substitution at nucleotide position 1843, causing the arginine (R) at amino acid position 615 to be replaced by a cysteine (C). 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
Benign
0.099
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.076
.;T;T;.;.;T
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.087
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.84
T;T;.;T;T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.25
T;T;T;T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Uncertain
2.6
M;M;M;.;.;.
PrimateAI
Benign
0.26
T
PROVEAN
Pathogenic
-5.4
D;D;D;D;D;D
REVEL
Benign
0.21
Sift
Benign
0.078
T;T;T;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
0.17
B;B;B;B;.;.
Vest4
0.37
MVP
0.53
MPC
0.23
ClinPred
0.91
D
GERP RS
5.8
Varity_R
0.20
gMVP
0.52

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: rs142693954; hg19: chr16-19483470; COSMIC: COSV54906522; COSMIC: COSV54906522; API