16-19440706-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001261841.2(TMC5):​c.668C>T​(p.Pro223Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TMC5
NM_001261841.2 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.33
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMC5NM_001261841.2 linkc.668C>T p.Pro223Leu missense_variant Exon 3 of 22 ENST00000542583.7 NP_001248770.1 Q6UXY8-1B7Z946
TMC5NM_001105248.1 linkc.668C>T p.Pro223Leu missense_variant Exon 3 of 22 NP_001098718.1 Q6UXY8-1
TMC5NM_001308161.1 linkc.668C>T p.Pro223Leu missense_variant Exon 3 of 21 NP_001295090.1 Q6UXY8F5GYU8B7Z5K3
TMC5NM_001105249.1 linkc.668C>T p.Pro223Leu missense_variant Exon 3 of 21 NP_001098719.1 Q6UXY8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMC5ENST00000542583.7 linkc.668C>T p.Pro223Leu missense_variant Exon 3 of 22 2 NM_001261841.2 ENSP00000446274.2 Q6UXY8-1
TMC5ENST00000381414.8 linkc.668C>T p.Pro223Leu missense_variant Exon 3 of 21 1 ENSP00000370822.4 Q6UXY8-2
TMC5ENST00000396229.6 linkc.668C>T p.Pro223Leu missense_variant Exon 3 of 22 5 ENSP00000379531.2 Q6UXY8-1
TMC5ENST00000541464.5 linkc.668C>T p.Pro223Leu missense_variant Exon 3 of 21 2 ENSP00000441227.1 F5GYU8

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000322
AC:
8
AN:
248468
Hom.:
0
AF XY:
0.0000370
AC XY:
5
AN XY:
134978
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000580
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000534
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
10
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
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:
0.0000162
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 02, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.668C>T (p.P223L) alteration is located in exon 3 (coding exon 1) of the TMC5 gene. This alteration results from a C to T substitution at nucleotide position 668, causing the proline (P) at amino acid position 223 to be replaced by a leucine (L). 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
0.13
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.29
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.096
.;.;T;T
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.88
D;D;D;.
M_CAP
Benign
0.020
T
MetaRNN
Uncertain
0.55
D;D;D;D
MetaSVM
Benign
-0.76
T
MutationAssessor
Uncertain
2.7
.;M;M;M
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.3
N;N;N;N
REVEL
Benign
0.18
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.53
MutPred
0.41
Gain of catalytic residue at P223 (P = 0.0669);Gain of catalytic residue at P223 (P = 0.0669);Gain of catalytic residue at P223 (P = 0.0669);Gain of catalytic residue at P223 (P = 0.0669);
MVP
0.74
MPC
0.66
ClinPred
0.51
D
GERP RS
5.3
Varity_R
0.073
gMVP
0.36

Splicing

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: rs772394226; hg19: chr16-19452028; API