rs145016347

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152468.5(TMC8):c.77T>C(p.Met26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,568,410 control chromosomes in the GnomAD database, including 1,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 82 hom., cov: 34)

Exomes 𝑓: 0.032 ( 931 hom. )

Consequence

TMC8
NM_152468.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.165

Variant links:

Genes affected

TMC8 (HGNC:20474): (transmembrane channel like 8) Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 8 predicted transmembrane domains and 3 leucine zipper motifs. [provided by RefSeq, Jul 2008]

TMC8 links:

TMC6 (HGNC:18021): (transmembrane channel like 6) Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 10 transmembrane domains and 2 leucine zipper motifs. [provided by RefSeq, Jul 2008]

TMC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019472837).

BP6

Variant 17-78131665-T-C is Benign according to our data. Variant chr17-78131665-T-C is described in ClinVar as [Benign]. Clinvar id is 1169102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78131665-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5 link	c.77T>C	p.Met26Thr	missense_variant	Exon 2 of 16	ENST00000318430.10	NP_689681.2	Q8IU68-1A0A024R8N8B3KXZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10 link	c.77T>C	p.Met26Thr	missense_variant	Exon 2 of 16	1	NM_152468.5	ENSP00000325561.4		Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.0238

AC:

3630

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00562

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0330

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.00693

Gnomad SAS

AF:

0.0819

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0305

Gnomad OTH

AF:

0.0339

GnomAD3 exomes

AF:

0.0321

AC:

5477

AN:

170648

Hom.:

155

AF XY:

0.0353

AC XY:

3258

AN XY:

92302

show subpopulations

Gnomad AFR exome

AF:

0.00378

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0399

Gnomad EAS exome

AF:

0.00669

Gnomad SAS exome

AF:

0.0777

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0312

Gnomad OTH exome

AF:

0.0363

GnomAD4 exome

AF:

0.0324

AC:

45814

AN:

1416076

Hom.:

931

Cov.:

AF XY:

0.0339

AC XY:

23745

AN XY:

700296

show subpopulations

Gnomad4 AFR exome

AF:

0.00583

Gnomad4 AMR exome

AF:

0.0239

Gnomad4 ASJ exome

AF:

0.0386

Gnomad4 EAS exome

AF:

0.00294

Gnomad4 SAS exome

AF:

0.0770

Gnomad4 FIN exome

AF:

0.0135

Gnomad4 NFE exome

AF:

0.0314

Gnomad4 OTH exome

AF:

0.0371

GnomAD4 genome

AF:

0.0238

AC:

3628

AN:

152334

Hom.:

Cov.:

AF XY:

0.0240

AC XY:

1788

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00563

Gnomad4 AMR

AF:

0.0329

Gnomad4 ASJ

AF:

0.0418

Gnomad4 EAS

AF:

0.00694

Gnomad4 SAS

AF:

0.0814

Gnomad4 FIN

AF:

0.0117

Gnomad4 NFE

AF:

0.0305

Gnomad4 OTH

AF:

0.0336

Alfa

AF:

0.0281

Hom.:

Bravo

AF:

0.0234

TwinsUK

AF:

0.0283

AC:

105

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.00355

AC:

ESP6500EA

AF:

0.0261

AC:

218

ExAC

AF:

0.0230

AC:

2654

Asia WGS

AF:

0.0430

AC:

148

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Epidermodysplasia verruciformis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.014

.;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.2

.;N

REVEL

Benign

0.15

Sift

Benign

0.097

.;T

Sift4G

Uncertain

0.021

D;D

Polyphen

0.0050

.;B

Vest4

0.11

MPC

1.7

ClinPred

0.013

GERP RS

3.1

Varity_R

0.17

gMVP

0.70

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