rs454138

Variant names:

• chr17-78141256-C-G
• rs454138
• NM_152468.5:c.*144C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-78141256-C-G
• chr17-78141256-C-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.*144C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 417,804 control chromosomes in the GnomAD database, including 88,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35005 hom., cov: 33)
  • Exomes 𝑓: 0.63 (53453 hom.)
• Consequence: TMC8 NM_152468.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.391
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-78141256-C-G is Benign according to our data. Variant chr17-78141256-C-G is described in ClinVar as Benign. ClinVar VariationId is 1243217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

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.*144C>G		3_prime_UTR	Exon 16 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.*144C>G		3_prime_UTR	Exon 16 of 16	ENSP00000325561.4	Q8IU68-1
	TMC8	ENST00000589691.1	TSL:1	c.*144C>G		3_prime_UTR	Exon 15 of 15	ENSP00000467482.1	Q8IU68-2
	TMC8	ENST00000972441.1		c.*144C>G		3_prime_UTR	Exon 16 of 16	ENSP00000642500.1

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102262 AN: 152038 Hom.: 34945 Cov.: 33

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.711

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.690

GnomAD4 exome AF: 0.631 AC: 167678 AN: 265648 Hom.: 53453 Cov.: 3 AF XY: 0.631 AC XY: 85544 AN XY: 135480

African (AFR) AF: 0.778 AC: 5620 AN: 7224

American (AMR) AF: 0.683 AC: 5722 AN: 8380

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 6847 AN: 9516

East Asian (EAS) AF: 0.522 AC: 12413 AN: 23776

South Asian (SAS) AF: 0.601 AC: 3717 AN: 6184

European-Finnish (FIN) AF: 0.659 AC: 14503 AN: 22000

Middle Eastern (MID) AF: 0.711 AC: 997 AN: 1402

European-Non Finnish (NFE) AF: 0.627 AC: 106372 AN: 169562

Other (OTH) AF: 0.653 AC: 11487 AN: 17604

GnomAD4 genome AF: 0.673 AC: 102384 AN: 152156 Hom.: 35005 Cov.: 33 AF XY: 0.674 AC XY: 50140 AN XY: 74382

African (AFR) AF: 0.780 AC: 32396 AN: 41542

American (AMR) AF: 0.711 AC: 10864 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2436 AN: 3470

East Asian (EAS) AF: 0.530 AC: 2746 AN: 5178

South Asian (SAS) AF: 0.597 AC: 2876 AN: 4820

European-Finnish (FIN) AF: 0.663 AC: 7015 AN: 10574

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.615 AC: 41802 AN: 67976

Other (OTH) AF: 0.693 AC: 1460 AN: 2106

Alfa AF: 0.647 Hom.: 3825

Bravo AF: 0.683

Asia WGS AF: 0.596 AC: 2073 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		0.39
Mutation Taster		=100/0	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: rs454138; hg19: chr17-76137337;