NM_152468.5:c.1725C>T

Variant names:

• chr17-78138634-C-T
• rs141186150
• NM_152468.5:c.1725C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_152468.5(TMC8):​c.1725C>T​(p.Val575Val) 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
• Publications: 1 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• epidermodysplasia verruciformis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.094).
• 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 VariationId is 456025.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152468.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	NM_152468.5	MANE Select	c.1725C>T	p.Val575Val	synonymous	Exon 14 of 16	NP_689681.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	ENST00000318430.10	TSL:1 MANE Select	c.1725C>T	p.Val575Val	synonymous	Exon 14 of 16	ENSP00000325561.4	Q8IU68-1
	TMC8	ENST00000589691.1	TSL:1	c.1056C>T	p.Val352Val	synonymous	Exon 13 of 15	ENSP00000467482.1	Q8IU68-2
	TMC8	ENST00000972441.1		c.1770C>T	p.Val590Val	synonymous	Exon 14 of 16	ENSP00000642500.1

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

GnomAD2 exomes AF: 0.00125 AC: 315 AN: 251046 AF XY: 0.00122

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 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

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00137 AC: 118 AN: 86258

European-Finnish (FIN) AF: 0.00141 AC: 75 AN: 53128

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00171 AC: 1904 AN: 1112002

Other (OTH) AF: 0.00121 AC: 73 AN: 60390

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

African (AFR) AF: 0.000168 AC: 7 AN: 41602

American (AMR) AF: 0.000979 AC: 15 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68034

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epidermodysplasia verruciformis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.4
DANN	Benign	0.77
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism

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