rs450474

Variant names:

• chr17-78133261-T-C
• rs450474
• NM_152468.5:c.532-145T>C

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.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
• Publications: 2 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=-0.82).
• BP6: Variant 17-78133261-T-C is Benign according to our data. Variant chr17-78133261-T-C is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.532-145T>C		intron_variant	Intron 5 of 15	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.532-145T>C		intron_variant	Intron 5 of 15	1	NM_152468.5	ENSP00000325561.4

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

African (AFR) AF: 0.290 AC: 8096 AN: 27878

American (AMR) AF: 0.116 AC: 5076 AN: 43884

Ashkenazi Jewish (ASJ) AF: 0.0886 AC: 2130 AN: 24028

East Asian (EAS) AF: 0.142 AC: 5408 AN: 38152

South Asian (SAS) AF: 0.108 AC: 8637 AN: 79826

European-Finnish (FIN) AF: 0.116 AC: 4555 AN: 39120

Middle Eastern (MID) AF: 0.0949 AC: 479 AN: 5046

European-Non Finnish (NFE) AF: 0.0950 AC: 81978 AN: 863376

Other (OTH) AF: 0.117 AC: 5931 AN: 50850

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

African (AFR) AF: 0.290 AC: 12038 AN: 41454

American (AMR) AF: 0.134 AC: 2042 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0920 AC: 319 AN: 3468

East Asian (EAS) AF: 0.159 AC: 822 AN: 5170

South Asian (SAS) AF: 0.117 AC: 567 AN: 4830

European-Finnish (FIN) AF: 0.116 AC: 1232 AN: 10598

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.0943 AC: 6411 AN: 67988

Other (OTH) AF: 0.142 AC: 300 AN: 2110

Alfa AF: 0.114 Hom.: 265

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

-

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.60
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs450474; hg19: chr17-76129342;