rs117156381

Positions:

• chr17-78133538-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152468.5(TMC8):​c.664C>T​(p.Arg222Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,611,934 control chromosomes in the GnomAD database, including 11 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 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: TMC8 NM_152468.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0360

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01226145).
• BP6: Variant 17-78133538-C-T is Benign according to our data. Variant chr17-78133538-C-T is described in ClinVar as [Benign]. Clinvar id is 526257.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (292/152276) while in subpopulation NFE AF= 0.00218 (148/67990). AF 95% confidence interval is 0.00189. There are 2 homozygotes in gnomad4. There are 159 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC8	NM_152468.5	c.664C>T	p.Arg222Trp	missense_variant	6/16	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.664C>T	p.Arg222Trp	missense_variant	6/16	1	NM_152468.5	ENSP00000325561.4

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152158 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00190 AC: 474 AN: 249708 Hom.: 3 AF XY: 0.00180 AC XY: 244 AN XY: 135284

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00187 AC: 2733 AN: 1459658 Hom.: 9 Cov.: 33 AF XY: 0.00179 AC XY: 1297 AN XY: 726272

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152276 Hom.: 2 Cov.: 33 AF XY: 0.00214 AC XY: 159 AN XY: 74462

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00175 Hom.: 1

Bravo AF: 0.00107

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00161 AC: 196

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

TMC8-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 30, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.30
MVP		0.68
MPC		0.17
ClinPred		0.058	T
GERP RS		3.1
Varity_R		0.18
gMVP		0.57

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

Other links and lift over

dbSNP: rs117156381; hg19: chr17-76129619; COSMIC: COSV59210444; COSMIC: COSV59210444;