chr17-78133849-G-C

Variant names:

• chr17-78133849-G-C
• rs8079824
• NM_152468.5:c.669-4G>C

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.669-4G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,613,042 control chromosomes in the GnomAD database, including 1,050 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 0.023 (79 hom., cov: 33)
  • Exomes 𝑓: 0.032 (971 hom.)
• Consequence: TMC8 NM_152468.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003684
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0950
• 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=-0.87).
• BP6: Variant 17-78133849-G-C is Benign according to our data. Variant chr17-78133849-G-C is described in ClinVar as Benign. ClinVar VariationId is 456027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.669-4G>C		splice_region_variant, intron_variant	Intron 6 of 15	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.669-4G>C		splice_region_variant, intron_variant	Intron 6 of 15	1	NM_152468.5	ENSP00000325561.4

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3507 AN: 152238 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.00528

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0307

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.00731

Gnomad SAS AF: 0.0967

Gnomad FIN AF: 0.0111

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0316 AC: 7859 AN: 248634 AF XY: 0.0354

Gnomad AFR exome AF: 0.00453

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.00708

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0315 AC: 46049 AN: 1460686 Hom.: 971 Cov.: 34 AF XY: 0.0335 AC XY: 24349 AN XY: 726614

African (AFR) AF: 0.00565 AC: 189 AN: 33476

American (AMR) AF: 0.0222 AC: 991 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 903 AN: 26136

East Asian (EAS) AF: 0.00317 AC: 126 AN: 39698

South Asian (SAS) AF: 0.0865 AC: 7463 AN: 86250

European-Finnish (FIN) AF: 0.0129 AC: 673 AN: 52348

Middle Eastern (MID) AF: 0.0648 AC: 373 AN: 5754

European-Non Finnish (NFE) AF: 0.0298 AC: 33155 AN: 1111946

Other (OTH) AF: 0.0361 AC: 2176 AN: 60360

GnomAD4 genome AF: 0.0230 AC: 3507 AN: 152356 Hom.: 79 Cov.: 33 AF XY: 0.0240 AC XY: 1789 AN XY: 74502

African (AFR) AF: 0.00529 AC: 220 AN: 41590

American (AMR) AF: 0.0307 AC: 470 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3472

East Asian (EAS) AF: 0.00733 AC: 38 AN: 5186

South Asian (SAS) AF: 0.0970 AC: 468 AN: 4824

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0288 AC: 1956 AN: 68034

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0202 Hom.: 20

Bravo AF: 0.0220

Asia WGS AF: 0.0480 AC: 165 AN: 3478

EpiCase AF: 0.0326

EpiControl AF: 0.0359

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

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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	-0.87
CADD	Benign	4.4
DANN	Benign	0.77
PhyloP100		-0.095
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.040		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: rs8079824; hg19: chr17-76129930;