rs450474

Positions:

• chr17-78133261-T-C

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.532-145T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,324,266 control chromosomes in the GnomAD database, including 9,674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2382 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7292 hom.)
• Consequence: TMC8 NM_152468.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.544

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 (BayesDel_noAF=-0.82).
• BP6: Variant 17-78133261-T-C is Benign according to our data. Variant chr17-78133261-T-C is described in ClinVar as [Benign]. Clinvar id is 1242180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC8	NM_152468.5	c.532-145T>C		intron_variant		ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.532-145T>C		intron_variant		1	NM_152468.5	ENSP00000325561	P2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23732 AN: 151990 Hom.: 2366 Cov.: 33

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.0920

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0943

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.104 AC: 122290 AN: 1172160 Hom.: 7292 AF XY: 0.103 AC XY: 61341 AN XY: 594310

Gnomad4 AFR exome AF: 0.290

Gnomad4 AMR exome AF: 0.116

Gnomad4 ASJ exome AF: 0.0886

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.0950

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.156 AC: 23794 AN: 152106 Hom.: 2382 Cov.: 33 AF XY: 0.156 AC XY: 11614 AN XY: 74356

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.0920

Gnomad4 EAS AF: 0.159

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.0943

Gnomad4 OTH AF: 0.142

Alfa AF: 0.114 Hom.: 263

Bravo AF: 0.165

Asia WGS AF: 0.163 AC: 566 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs450474; hg19: chr17-76129342;