rs7221365

Positions:

• chr17-78138747-C-A
• chr17-78138747-C-G
• chr17-78138747-C-T

Variant summary

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

The ENST00000318430.10(TMC8):​c.1823+15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,602,978 control chromosomes in the GnomAD database, including 254,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30250 hom., cov: 34)
  • Exomes 𝑓: 0.55 (224748 hom.)
• Consequence: TMC8 ENST00000318430.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.16

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=-0.84).
• BP6: Variant 17-78138747-C-A is Benign according to our data. Variant chr17-78138747-C-A is described in ClinVar as [Benign]. Clinvar id is 403549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78138747-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC8	NM_152468.5	c.1823+15C>A		intron_variant		ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.1823+15C>A		intron_variant		1	NM_152468.5	ENSP00000325561	P2

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94523 AN: 152028 Hom.: 30191 Cov.: 34

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.622

GnomAD3 exomes AF: 0.580 AC: 140372 AN: 241890 Hom.: 41605 AF XY: 0.575 AC XY: 75650 AN XY: 131654

Gnomad AFR exome AF: 0.762

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.440

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.589

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.554 AC: 803419 AN: 1450832 Hom.: 224748 Cov.: 62 AF XY: 0.554 AC XY: 399931 AN XY: 722072

Gnomad4 AFR exome AF: 0.765

Gnomad4 AMR exome AF: 0.641

Gnomad4 ASJ exome AF: 0.646

Gnomad4 EAS exome AF: 0.448

Gnomad4 SAS exome AF: 0.539

Gnomad4 FIN exome AF: 0.582

Gnomad4 NFE exome AF: 0.544

Gnomad4 OTH exome AF: 0.575

GnomAD4 genome AF: 0.622 AC: 94646 AN: 152146 Hom.: 30250 Cov.: 34 AF XY: 0.622 AC XY: 46288 AN XY: 74402

Gnomad4 AFR AF: 0.756

Gnomad4 AMR AF: 0.642

Gnomad4 ASJ AF: 0.648

Gnomad4 EAS AF: 0.437

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.597

Gnomad4 NFE AF: 0.557

Gnomad4 OTH AF: 0.627

Alfa AF: 0.584 Hom.: 33098

Bravo AF: 0.633

Asia WGS AF: 0.532 AC: 1850 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 77. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

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

Epidermodysplasia verruciformis, susceptibility to, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.11
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7221365; hg19: chr17-76134828; COSMIC: COSV59209064; COSMIC: COSV59209064;