17-78131657-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_152468.5(TMC8):c.69G>A(p.Glu23=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,565,190 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 34)
  • Exomes 𝑓: 0.0080 (51 hom.)
• Consequence: TMC8 NM_152468.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.570

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]

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 17-78131657-G-A is Benign according to our data. Variant chr17-78131657-G-A is described in ClinVar as [Benign]. Clinvar id is 1166987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.57 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00593 (904/152376) while in subpopulation NFE AF= 0.00851 (579/68042). AF 95% confidence interval is 0.00794. There are 8 homozygotes in gnomad4. There are 421 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5	c.69G>A	p.Glu23=	synonymous_variant	2/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.69G>A	p.Glu23=	synonymous_variant	2/16	1	NM_152468.5	P2
TMC6	ENST00000322914.7	c.-75+684C>T		intron_variant		1		P1
TMC8	ENST00000589691.1	c.-372+252G>A		intron_variant		1		A2
TMC8	ENST00000590799.5	n.451G>A		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152258 Hom.: 8 Cov.: 34

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00851

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00650 AC: 1083 AN: 166524 Hom.: 8 AF XY: 0.00633 AC XY: 569 AN XY: 89830

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00185

Gnomad FIN exome AF: 0.00324

Gnomad NFE exome AF: 0.00936

Gnomad OTH exome AF: 0.00611

GnomAD4 exome AF: 0.00798 AC: 11281 AN: 1412814 Hom.: 51 Cov.: 31 AF XY: 0.00792 AC XY: 5531 AN XY: 698380

Gnomad4 AFR exome AF: 0.00154

Gnomad4 AMR exome AF: 0.00330

Gnomad4 ASJ exome AF: 0.0301

Gnomad4 EAS exome AF: 0.0000537

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.00387

Gnomad4 NFE exome AF: 0.00873

Gnomad4 OTH exome AF: 0.00788

GnomAD4 genome AF: 0.00593 AC: 904 AN: 152376 Hom.: 8 Cov.: 34 AF XY: 0.00565 AC XY: 421 AN XY: 74512

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00851

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00941 Hom.: 3

Bravo AF: 0.00566

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

TMC8: BP4, BP7, BS1, BS2 -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.97

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: rs35748721; hg19: chr17-76127738; COSMIC: COSV100130571; COSMIC: COSV100130571;