rs17773842

Positions:

• chr17-78139321-G-A

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.1902+81G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,516,928 control chromosomes in the GnomAD database, including 69,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5019 hom., cov: 33)
  • Exomes 𝑓: 0.30 (64627 hom.)
• Consequence: TMC8 NM_152468.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35

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=-0.8).
• BP6: Variant 17-78139321-G-A is Benign according to our data. Variant chr17-78139321-G-A is described in ClinVar as [Benign]. Clinvar id is 1238978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5	c.1902+81G>A		intron_variant		ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.1902+81G>A		intron_variant		1	NM_152468.5	P2

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34112 AN: 152046 Hom.: 5022 Cov.: 33

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.298 AC: 406963 AN: 1364764 Hom.: 64627 AF XY: 0.298 AC XY: 203272 AN XY: 682356

Gnomad4 AFR exome AF: 0.0508

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.328

Gnomad4 OTH exome AF: 0.285

GnomAD4 genome AF: 0.224 AC: 34095 AN: 152164 Hom.: 5019 Cov.: 33 AF XY: 0.220 AC XY: 16400 AN XY: 74396

Gnomad4 AFR AF: 0.0560

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.338

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.328

Gnomad4 OTH AF: 0.248

Alfa AF: 0.299 Hom.: 3444

Bravo AF: 0.212

Asia WGS AF: 0.112 AC: 393 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.7
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17773842; hg19: chr17-76135402;