NM_152468.5:c.1902+81G>A

Variant names:

• chr17-78139321-G-A
• rs17773842
• NM_152468.5:c.1902+81G>A

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+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:3
• Conservation: PhyloP100: 1.35
• Publications: 9 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=-0.8).
• BP6: Variant 17-78139321-G-A is Benign according to our data. Variant chr17-78139321-G-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.1902+81G>A		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+81G>A		intron_variant	Intron 15 of 15	1	NM_152468.5	ENSP00000325561.4

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

African (AFR) AF: 0.0508 AC: 1599 AN: 31472

American (AMR) AF: 0.157 AC: 6691 AN: 42572

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 8789 AN: 25458

East Asian (EAS) AF: 0.0115 AC: 444 AN: 38726

South Asian (SAS) AF: 0.221 AC: 18462 AN: 83598

European-Finnish (FIN) AF: 0.298 AC: 13787 AN: 46228

Middle Eastern (MID) AF: 0.346 AC: 1451 AN: 4198

European-Non Finnish (NFE) AF: 0.328 AC: 339460 AN: 1035304

Other (OTH) AF: 0.285 AC: 16280 AN: 57208

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

African (AFR) AF: 0.0560 AC: 2329 AN: 41558

American (AMR) AF: 0.216 AC: 3297 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3468

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5180

South Asian (SAS) AF: 0.206 AC: 997 AN: 4830

European-Finnish (FIN) AF: 0.289 AC: 3064 AN: 10588

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.328 AC: 22257 AN: 67936

Other (OTH) AF: 0.248 AC: 524 AN: 2110

Alfa AF: 0.291 Hom.: 4882

Bravo AF: 0.212

Asia WGS AF: 0.112 AC: 393 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 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.7
DANN	Benign	0.65
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17773842; hg19: chr17-76135402;