rs79153946

chr17-78113215-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127198.5(TMC6):c.2355-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,552,758 control chromosomes in the GnomAD database, including 266 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (11 hom., cov: 33)
  • Exomes 𝑓: 0.018 (255 hom.)
• Consequence: TMC6 NM_001127198.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004547
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-78113215-C-T is Benign according to our data. Variant chr17-78113215-C-T is described in ClinVar as [Benign]. Clinvar id is 456014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78113215-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1697/152292) while in subpopulation NFE AF= 0.0185 (1259/68034). AF 95% confidence interval is 0.0177. There are 11 homozygotes in gnomad4. There are 777 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.2355-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.2355-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1696 AN: 152174 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.0116 AC: 1854 AN: 159792 Hom.: 14 AF XY: 0.0119 AC XY: 1003 AN XY: 84600

Gnomad AFR exome AF: 0.00370

Gnomad AMR exome AF: 0.00598

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.0000804

Gnomad SAS exome AF: 0.00825

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0176 AC: 24708 AN: 1400466 Hom.: 255 Cov.: 31 AF XY: 0.0175 AC XY: 12101 AN XY: 690776

Gnomad4 AFR exome AF: 0.00249

Gnomad4 AMR exome AF: 0.00608

Gnomad4 ASJ exome AF: 0.00736

Gnomad4 EAS exome AF: 0.0000544

Gnomad4 SAS exome AF: 0.00867

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.0111 AC: 1697 AN: 152292 Hom.: 11 Cov.: 33 AF XY: 0.0104 AC XY: 777 AN XY: 74448

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00727

Gnomad4 FIN AF: 0.00980

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.0153 Hom.: 11

Bravo AF: 0.0107

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: 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 31, 2024

- -

TMC6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

This variant is classified as 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	-0.79
Cadd	Benign	0.60
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0
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: rs79153946; hg19: chr17-76109296;