chr17-78141852-T-G

Variant names:

• chr17-78141852-T-G
• rs11654773
• NM_152468.5:c.*740T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152468.5(TMC8):​c.*740T>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 0.0606 in 152,380 control chromosomes in the GnomAD database, including 409 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.061 (409 hom., cov: 34)
  • Exomes 𝑓: 0.025 (0 hom.)
• Consequence: TMC8 NM_152468.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0580
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• epidermodysplasia verruciformis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.115 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	NM_152468.5	MANE Select	c.*740T>G		3_prime_UTR	Exon 16 of 16	NP_689681.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	ENST00000318430.10	TSL:1 MANE Select	c.*740T>G		3_prime_UTR	Exon 16 of 16	ENSP00000325561.4
	TMC8	ENST00000589691.1	TSL:1	c.*740T>G		3_prime_UTR	Exon 15 of 15	ENSP00000467482.1
	TMC8	ENST00000698567.1		n.2583T>G		non_coding_transcript_exon	Exon 13 of 13

Frequencies

GnomAD3 genomes AF: 0.0605 AC: 9210 AN: 152222 Hom.: 410 Cov.: 34

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.00807

Gnomad SAS AF: 0.0962

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0380

Gnomad OTH AF: 0.0550

GnomAD4 exome AF: 0.0250 AC: 1 AN: 40 Hom.: 0 Cov.: 0 AF XY: 0.0357 AC XY: 1 AN XY: 28

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0385 AC: 1 AN: 26

Other (OTH) AF: 0.00 AC: 0 AN: 6

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0606 AC: 9231 AN: 152340 Hom.: 409 Cov.: 34 AF XY: 0.0605 AC XY: 4511 AN XY: 74502

African (AFR) AF: 0.118 AC: 4894 AN: 41570

American (AMR) AF: 0.0456 AC: 698 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3470

East Asian (EAS) AF: 0.00809 AC: 42 AN: 5192

South Asian (SAS) AF: 0.0963 AC: 465 AN: 4830

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10626

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0380 AC: 2586 AN: 68022

Other (OTH) AF: 0.0563 AC: 119 AN: 2114

Alfa AF: 0.0451 Hom.: 240

Bravo AF: 0.0622

Asia WGS AF: 0.0630 AC: 217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.0
DANN	Benign	0.41
PhyloP100		-0.058
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: rs11654773; hg19: chr17-76137933;