17-78131402-C-T

Variant names:

• chr17-78131402-C-T
• rs452483
• NM_152468.5:c.-187C>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.-187C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0925 in 772,482 control chromosomes in the GnomAD database, including 3,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (604 hom., cov: 34)
  • Exomes 𝑓: 0.095 (2965 hom.)
• Consequence: TMC8 NM_152468.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.144
• Publications: 5 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]

TMC6 (HGNC:18021): (transmembrane channel like 6) 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 10 transmembrane domains and 2 leucine zipper motifs. [provided by RefSeq, Jul 2008]

TMC6 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermodysplasia verruciformis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, 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 17-78131402-C-T is Benign according to our data. Variant chr17-78131402-C-T is described in ClinVar as [Benign]. Clinvar id is 1263402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.-187C>T		5_prime_UTR_variant	Exon 2 of 16	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.-187C>T		5_prime_UTR_variant	Exon 2 of 16	1	NM_152468.5	ENSP00000325561.4

Frequencies

GnomAD3 genomes AF: 0.0814 AC: 12379 AN: 152138 Hom.: 603 Cov.: 34

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0787

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0913

GnomAD4 exome AF: 0.0953 AC: 59078 AN: 620226 Hom.: 2965 Cov.: 8 AF XY: 0.0952 AC XY: 30727 AN XY: 322906

African (AFR) AF: 0.0329 AC: 516 AN: 15694

American (AMR) AF: 0.0695 AC: 1556 AN: 22384

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 1632 AN: 16162

East Asian (EAS) AF: 0.0822 AC: 2617 AN: 31830

South Asian (SAS) AF: 0.0914 AC: 4911 AN: 53724

European-Finnish (FIN) AF: 0.108 AC: 3288 AN: 30440

Middle Eastern (MID) AF: 0.0757 AC: 180 AN: 2378

European-Non Finnish (NFE) AF: 0.0996 AC: 41429 AN: 415752

Other (OTH) AF: 0.0926 AC: 2949 AN: 31862

GnomAD4 genome AF: 0.0813 AC: 12379 AN: 152256 Hom.: 604 Cov.: 34 AF XY: 0.0820 AC XY: 6104 AN XY: 74440

African (AFR) AF: 0.0380 AC: 1578 AN: 41564

American (AMR) AF: 0.0788 AC: 1205 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3470

East Asian (EAS) AF: 0.113 AC: 583 AN: 5176

South Asian (SAS) AF: 0.0921 AC: 445 AN: 4830

European-Finnish (FIN) AF: 0.107 AC: 1140 AN: 10612

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6816 AN: 67992

Other (OTH) AF: 0.0908 AC: 192 AN: 2114

Alfa AF: 0.0885 Hom.: 198

Bravo AF: 0.0774

Asia WGS AF: 0.0960 AC: 334 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	-0.86
CADD	Benign	7.2
DANN	Benign	0.88
PhyloP100		0.14
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs452483; hg19: chr17-76127483; COSMIC: COSV59210781; COSMIC: COSV59210781;