17-78138569-G-T

Variant names:

• chr17-78138569-G-T
• rs11651864
• NM_152468.5:c.1665-5G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152468.5(TMC8):​c.1665-5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,613,736 control chromosomes in the GnomAD database, including 1,466 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (109 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1357 hom.)
• Consequence: TMC8 NM_152468.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001925
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.385
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• epidermodysplasia verruciformis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-78138569-G-T is Benign according to our data. Variant chr17-78138569-G-T is described in ClinVar as Benign. ClinVar VariationId is 456024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.1665-5G>T		splice_region_variant, intron_variant	Intron 13 of 15	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.1665-5G>T		splice_region_variant, intron_variant	Intron 13 of 15	1	NM_152468.5	ENSP00000325561.4

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4979 AN: 152174 Hom.: 110 Cov.: 33

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.00808

Gnomad SAS AF: 0.0978

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0382

GnomAD2 exomes AF: 0.0376 AC: 9428 AN: 250772 AF XY: 0.0409

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.0250

Gnomad ASJ exome AF: 0.0400

Gnomad EAS exome AF: 0.00931

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0376

Gnomad OTH exome AF: 0.0402

GnomAD4 exome AF: 0.0392 AC: 57233 AN: 1461444 Hom.: 1357 Cov.: 33 AF XY: 0.0407 AC XY: 29606 AN XY: 727004

African (AFR) AF: 0.0223 AC: 747 AN: 33480

American (AMR) AF: 0.0243 AC: 1086 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0391 AC: 1023 AN: 26136

East Asian (EAS) AF: 0.00370 AC: 147 AN: 39700

South Asian (SAS) AF: 0.0843 AC: 7269 AN: 86258

European-Finnish (FIN) AF: 0.0214 AC: 1136 AN: 52992

Middle Eastern (MID) AF: 0.0659 AC: 380 AN: 5768

European-Non Finnish (NFE) AF: 0.0385 AC: 42772 AN: 1112000

Other (OTH) AF: 0.0443 AC: 2673 AN: 60388

GnomAD4 genome AF: 0.0327 AC: 4985 AN: 152292 Hom.: 109 Cov.: 33 AF XY: 0.0330 AC XY: 2454 AN XY: 74466

African (AFR) AF: 0.0229 AC: 953 AN: 41570

American (AMR) AF: 0.0300 AC: 459 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 154 AN: 3470

East Asian (EAS) AF: 0.00810 AC: 42 AN: 5184

South Asian (SAS) AF: 0.0978 AC: 472 AN: 4824

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10626

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2556 AN: 68002

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0270 Hom.: 40

Bravo AF: 0.0312

Asia WGS AF: 0.0590 AC: 204 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0433

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
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.39
PhyloP100		-0.39
Mutation Taster		=48/52	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs11651864; hg19: chr17-76134650; COSMIC: COSV107384605; COSMIC: COSV107384605;