17-78134906-G-T

Variant names:

• chr17-78134906-G-T
• rs112802399
• NM_152468.5:c.1024G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152468.5(TMC8):​c.1024G>T​(p.Gly342Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0289 in 1,614,058 control chromosomes in the GnomAD database, including 832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (38 hom., cov: 33)
  • Exomes 𝑓: 0.030 (794 hom.)
• Consequence: TMC8 NM_152468.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.94

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032699704).
• BP6: Variant 17-78134906-G-T is Benign according to our data. Variant chr17-78134906-G-T is described in ClinVar as [Benign]. Clinvar id is 456020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78134906-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.1024G>T	p.Gly342Trp	missense_variant	Exon 9 of 16	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.1024G>T	p.Gly342Trp	missense_variant	Exon 9 of 16	1	NM_152468.5	ENSP00000325561.4

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2882 AN: 152122 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0612

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0246 AC: 6172 AN: 251158 Hom.: 125 AF XY: 0.0279 AC XY: 3784 AN XY: 135854

Gnomad AFR exome AF: 0.00573

Gnomad AMR exome AF: 0.00697

Gnomad ASJ exome AF: 0.0437

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0574

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0299 AC: 43733 AN: 1461818 Hom.: 794 Cov.: 34 AF XY: 0.0310 AC XY: 22514 AN XY: 727204

Gnomad4 AFR exome AF: 0.00478

Gnomad4 AMR exome AF: 0.00727

Gnomad4 ASJ exome AF: 0.0430

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0568

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0312

Gnomad4 OTH exome AF: 0.0289

GnomAD4 genome AF: 0.0189 AC: 2878 AN: 152240 Hom.: 38 Cov.: 33 AF XY: 0.0184 AC XY: 1372 AN XY: 74446

Gnomad4 AFR AF: 0.00571

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0611

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0271

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0268 Hom.: 86

Bravo AF: 0.0167

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0301 AC: 116

ESP6500AA AF: 0.00885 AC: 39

ESP6500EA AF: 0.0290 AC: 249

ExAC AF: 0.0246 AC: 2989

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0258

EpiControl AF: 0.0258

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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	Pathogenic	0.74
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.17
Sift	Uncertain	0.029	D;.
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;.
Vest4		0.27
MPC		0.74
ClinPred		0.015	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.65

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: rs112802399; hg19: chr17-76130987;