17-78131402-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.144

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
TMC8	NM_152468.5	c.-187C>T		5_prime_UTR_variant	2/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.-187C>T		5_prime_UTR_variant	2/16	1	NM_152468.5	P2

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

Gnomad4 AFR exome AF: 0.0329

Gnomad4 AMR exome AF: 0.0695

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.0822

Gnomad4 SAS exome AF: 0.0914

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.0996

Gnomad4 OTH exome AF: 0.0926

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

Gnomad4 AFR AF: 0.0380

Gnomad4 AMR AF: 0.0788

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.0921

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.0908

Alfa AF: 0.0866 Hom.: 80

Bravo AF: 0.0774

Asia WGS AF: 0.0960 AC: 334 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	7.2
Dann	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs452483; hg19: chr17-76127483; COSMIC: COSV59210781; COSMIC: COSV59210781;