rs199765733

chr17-78113538-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001127198.5(TMC6):c.2354+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,613,782 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (3 hom.)
• Consequence: TMC6 NM_001127198.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.10

Genes affected

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-78113538-G-A is Benign according to our data. Variant chr17-78113538-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 456013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00109 (166/152068) while in subpopulation NFE AF= 0.00149 (101/67966). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.2354+10C>T		intron_variant		ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.2354+10C>T		intron_variant		2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 151950 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000919

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00103 AC: 258 AN: 251090 Hom.: 1 AF XY: 0.000906 AC XY: 123 AN XY: 135828

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000925

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000884 AC: 1292 AN: 1461714 Hom.: 3 Cov.: 31 AF XY: 0.000904 AC XY: 657 AN XY: 727150

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000825

Gnomad4 NFE exome AF: 0.000957

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74354

Gnomad4 AFR AF: 0.000917

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00100

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

TMC6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.28
Dann	Benign	0.56

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: rs199765733; hg19: chr17-76109619;