17-78139331-G-T

Variant names:

• chr17-78139331-G-T
• rs17773854
• NM_152468.5:c.1902+91G>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.1902+91G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 1,459,682 control chromosomes in the GnomAD database, including 150,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14788 hom., cov: 32)
  • Exomes 𝑓: 0.45 (135368 hom.)
• Consequence: TMC8 NM_152468.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.47
• Publications: 12 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=-0.86).
• BP6: Variant 17-78139331-G-T is Benign according to our data. Variant chr17-78139331-G-T is described in ClinVar as Benign. ClinVar VariationId is 1250684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.1902+91G>T		intron_variant	Intron 15 of 15	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.1902+91G>T		intron_variant	Intron 15 of 15	1	NM_152468.5	ENSP00000325561.4

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65946 AN: 151874 Hom.: 14782 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.455

GnomAD4 exome AF: 0.451 AC: 589602 AN: 1307690 Hom.: 135368 AF XY: 0.452 AC XY: 295358 AN XY: 653892

African (AFR) AF: 0.400 AC: 12077 AN: 30184

American (AMR) AF: 0.276 AC: 11274 AN: 40868

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 13756 AN: 24908

East Asian (EAS) AF: 0.228 AC: 8647 AN: 37922

South Asian (SAS) AF: 0.405 AC: 33159 AN: 81782

European-Finnish (FIN) AF: 0.478 AC: 20768 AN: 43418

Middle Eastern (MID) AF: 0.557 AC: 2207 AN: 3962

European-Non Finnish (NFE) AF: 0.468 AC: 462741 AN: 989524

Other (OTH) AF: 0.453 AC: 24973 AN: 55122

GnomAD4 genome AF: 0.434 AC: 65990 AN: 151992 Hom.: 14788 Cov.: 32 AF XY: 0.430 AC XY: 31964 AN XY: 74300

African (AFR) AF: 0.398 AC: 16483 AN: 41436

American (AMR) AF: 0.363 AC: 5547 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1902 AN: 3468

East Asian (EAS) AF: 0.231 AC: 1194 AN: 5172

South Asian (SAS) AF: 0.394 AC: 1902 AN: 4824

European-Finnish (FIN) AF: 0.485 AC: 5127 AN: 10570

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32179 AN: 67936

Other (OTH) AF: 0.457 AC: 964 AN: 2110

Alfa AF: 0.467 Hom.: 27873

Bravo AF: 0.425

Asia WGS AF: 0.331 AC: 1153 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.4
DANN	Benign	0.58
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs17773854; hg19: chr17-76135412;