17-78131566-AGCCTCTACCCGTGCCCGCCGAGATGCT-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_152468.5(TMC8):c.-20_7delCTCTACCCGTGCCCGCCGAGATGCTGC(p.Met1_Leu3del) variant causes a start lost, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000864 in 1,388,910 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

TMC8
NM_152468.5 start_lost, conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14

Publications

0 publications found

Variant links:

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 links:

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]

TMC6 Gene-Disease associations (from GenCC):

epidermodysplasia verruciformis, susceptibility to, 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
epidermodysplasia verruciformis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

TMC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5 link	c.-20_7delCTCTACCCGTGCCCGCCGAGATGCTGC	p.Met1_Leu3del	start_lost, conservative_inframe_deletion	Exon 2 of 16	ENST00000318430.10	NP_689681.2	Q8IU68-1A0A024R8N8B3KXZ8
TMC8	NM_152468.5 link	c.-20_7delCTCTACCCGTGCCCGCCGAGATGCTGC		5_prime_UTR_variant	Exon 2 of 16	ENST00000318430.10	NP_689681.2	Q8IU68-1A0A024R8N8B3KXZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10 link	c.-20_7delCTCTACCCGTGCCCGCCGAGATGCTGC	p.Met1_Leu3del	start_lost, conservative_inframe_deletion	Exon 2 of 16	1	NM_152468.5	ENSP00000325561.4		Q8IU68-1
TMC8	ENST00000318430.10 link	c.-20_7delCTCTACCCGTGCCCGCCGAGATGCTGC		5_prime_UTR_variant	Exon 2 of 16	1	NM_152468.5	ENSP00000325561.4		Q8IU68-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000734

AC:

AN:

136176

AF XY:

0.0000135

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000198

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000864

AC:

AN:

1388910

Hom.:

AF XY:

0.00000584

AC XY:

AN XY:

685342

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31504

American (AMR)

AF:

0.00

AC:

AN:

35668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25136

East Asian (EAS)

AF:

0.00

AC:

AN:

35722

South Asian (SAS)

AF:

0.00

AC:

AN:

79124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4164

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1078504

Other (OTH)

AF:

0.00

AC:

AN:

57746

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000001), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.383

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epidermodysplasia verruciformis

Uncertain:1

May 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with TMC8-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change affects the initiator methionine of the TMC8 mRNA. The next in-frame methionine is located at codon 26. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=115/85

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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17-78131566-AGCCTCTACCCGTGCCCGCCGAGATGCT-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over