rs61739261

chr17-78121066-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_001127198.5(TMC6):c.1482C>T(p.Ala494=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,613,194 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (49 hom.)
• Consequence: TMC6 NM_001127198.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 17-78121066-G-A is Benign according to our data. Variant chr17-78121066-G-A is described in ClinVar as [Benign]. Clinvar id is 526255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2030/152270) while in subpopulation AFR AF= 0.0405 (1681/41534). AF 95% confidence interval is 0.0389. There are 45 homozygotes in gnomad4. There are 958 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.1482C>T	p.Ala494=	synonymous_variant	12/20	ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.1482C>T	p.Ala494=	synonymous_variant	12/20	2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2027 AN: 152152 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00528 AC: 1320 AN: 249976 Hom.: 16 AF XY: 0.00484 AC XY: 656 AN XY: 135556

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.00446

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00770

GnomAD4 exome AF: 0.00281 AC: 4112 AN: 1460924 Hom.: 49 Cov.: 32 AF XY: 0.00280 AC XY: 2033 AN XY: 726776

Gnomad4 AFR exome AF: 0.0430

Gnomad4 AMR exome AF: 0.00494

Gnomad4 ASJ exome AF: 0.0346

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000937

Gnomad4 OTH exome AF: 0.00684

GnomAD4 genome AF: 0.0133 AC: 2030 AN: 152270 Hom.: 45 Cov.: 32 AF XY: 0.0129 AC XY: 958 AN XY: 74444

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00967 Hom.: 8

Bravo AF: 0.0148

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00320

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

Oct 02, 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	-0.50
Cadd	Benign	1.6
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61739261; hg19: chr17-76117147;