rs141186150

chr17-78138634-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_152468.5(TMC8):c.1725C>T(p.Val575=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,978 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: TMC8 NM_152468.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.392

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 17-78138634-C-T is Benign according to our data. Variant chr17-78138634-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456025.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-78138634-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00117 (179/152394) while in subpopulation NFE AF= 0.00187 (127/68034). AF 95% confidence interval is 0.0016. There are 2 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5	c.1725C>T	p.Val575=	synonymous_variant	14/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.1725C>T	p.Val575=	synonymous_variant	14/16	1	NM_152468.5	P2

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152276 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00125 AC: 315 AN: 251046 Hom.: 1 AF XY: 0.00122 AC XY: 165 AN XY: 135776

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00153 AC: 2231 AN: 1461584 Hom.: 4 Cov.: 33 AF XY: 0.00154 AC XY: 1120 AN XY: 727096

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00117 AC: 179 AN: 152394 Hom.: 2 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74526

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000979

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00154 Hom.: 1

Bravo AF: 0.000997

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00142

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermodysplasia verruciformis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	3.4
Dann	Benign	0.77

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: rs141186150; hg19: chr17-76134715; COSMIC: COSV100573700; COSMIC: COSV100573700;