Genetic Variant TMC5:p.Pro223Leu (chr16-19440706-C-T) – ACMG Classification: Uncertain_significance (2 pts)

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

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]

TMC5 links:

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
TMC5	NM_001261841.2 link	c.668C>T	p.Pro223Leu	missense_variant	Exon 3 of 22	ENST00000542583.7	NP_001248770.1	Q6UXY8-1B7Z946
TMC5	NM_001105248.1 link	c.668C>T	p.Pro223Leu	missense_variant	Exon 3 of 22		NP_001098718.1	Q6UXY8-1
TMC5	NM_001308161.1 link	c.668C>T	p.Pro223Leu	missense_variant	Exon 3 of 21		NP_001295090.1	Q6UXY8F5GYU8B7Z5K3
TMC5	NM_001105249.1 link	c.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	UniProt
TMC5	ENST00000542583.7 link	c.668C>T	p.Pro223Leu	missense_variant	Exon 3 of 22	2	NM_001261841.2	ENSP00000446274.2	Q6UXY8-1
TMC5	ENST00000381414.8 link	c.668C>T	p.Pro223Leu	missense_variant	Exon 3 of 21	1		ENSP00000370822.4	Q6UXY8-2
TMC5	ENST00000396229.6 link	c.668C>T	p.Pro223Leu	missense_variant	Exon 3 of 22	5		ENSP00000379531.2	Q6UXY8-1
TMC5	ENST00000541464.5 link	c.668C>T	p.Pro223Leu	missense_variant	Exon 3 of 21	2		ENSP00000441227.1	F5GYU8

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

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:

AN:

248468

Hom.:

AF XY:

0.0000370

AC XY:

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:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

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:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

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:

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

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.096

.;.;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;D;D;.

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.55

D;D;D;D

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.7

.;M;M;M

PrimateAI

Benign

0.39

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over