Genetic Variant TMC5:p.Arg380Lys (chr16-19460325-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001261841.2(TMC5):c.1139G>A(p.Arg380Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00367 in 1,612,256 control chromosomes in the GnomAD database, including 15 homozygotes. 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 14 hom. )

Consequence

TMC5
NM_001261841.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.28

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:

ENSG00000260592 (HGNC:):

ENSG00000260592 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042259097).

BP6

Variant 16-19460325-G-A is Benign according to our data. Variant chr16-19460325-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2646275.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC5	NM_001261841.2 link	c.1139G>A	p.Arg380Lys	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
TMC5	ENST00000542583.7 link	c.1139G>A	p.Arg380Lys	missense_variant	Exon 6 of 22	2	NM_001261841.2	ENSP00000446274.2		Q6UXY8-1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

378

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00429

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00220

AC:

551

AN:

250734

Hom.:

AF XY:

0.00238

AC XY:

323

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00395

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00380

AC:

5544

AN:

1459974

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

2681

AN XY:

726434

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.000862

Gnomad4 NFE exome

AF:

0.00462

Gnomad4 OTH exome

AF:

0.00395

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152282

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

182

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00429

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00349

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00227

AC:

275

EpiCase

AF:

0.00557

EpiControl

AF:

0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMC5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

.;.;T;T;.;.;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

D;T;T;.;T;T;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.0042

T;T;T;T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.0

.;M;M;M;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.10

T;T;T;T;T;T;T

Sift4G

Benign

0.27

T;T;T;T;T;T;T

Polyphen

0.64

P;B;B;B;P;.;.

Vest4

0.18

MVP

0.46

MPC

0.30

ClinPred

0.012

GERP RS

5.3

Varity_R

0.24

gMVP

0.49

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.

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