rs143140501

Variant names:

• chr17-78117791-G-A
• rs143140501
• NM_001127198.5:c.2021+11C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-78117791-G-A
• chr17-78117791-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001127198.5(TMC6):​c.2021+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,602,370 control chromosomes in the GnomAD database, including 695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (58 hom., cov: 33)
  • Exomes 𝑓: 0.028 (637 hom.)
• Consequence: TMC6 NM_001127198.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.112
• Publications: 0 publications found

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]

TMC6 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• epidermodysplasia verruciformis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-78117791-G-A is Benign according to our data. Variant chr17-78117791-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403544.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 = 0.0246 (3739/151906) while in subpopulation NFE AF = 0.0325 (2210/67926). AF 95% confidence interval is 0.0314. There are 58 homozygotes in GnomAd4. There are 1815 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 58 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127198.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	NM_001127198.5	MANE Select	c.2021+11C>T		intron	N/A	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.2021+11C>T		intron	N/A	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.2021+11C>T		intron	N/A	NP_001361525.1	Q7Z403-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	ENST00000590602.6	TSL:2 MANE Select	c.2021+11C>T		intron	N/A	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.2021+11C>T		intron	N/A	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.2021+11C>T		intron	N/A	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3744 AN: 151786 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0316

Gnomad ASJ AF: 0.0214

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0307

GnomAD2 exomes AF: 0.0228 AC: 5227 AN: 229718 AF XY: 0.0233

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.000173

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0263

GnomAD4 exome AF: 0.0284 AC: 41172 AN: 1450464 Hom.: 637 Cov.: 32 AF XY: 0.0280 AC XY: 20171 AN XY: 720608

African (AFR) AF: 0.0126 AC: 417 AN: 33212

American (AMR) AF: 0.0181 AC: 790 AN: 43718

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 602 AN: 25862

East Asian (EAS) AF: 0.0000510 AC: 2 AN: 39198

South Asian (SAS) AF: 0.0109 AC: 920 AN: 84686

European-Finnish (FIN) AF: 0.0284 AC: 1456 AN: 51332

Middle Eastern (MID) AF: 0.0391 AC: 224 AN: 5722

European-Non Finnish (NFE) AF: 0.0318 AC: 35179 AN: 1106812

Other (OTH) AF: 0.0264 AC: 1582 AN: 59922

GnomAD4 genome AF: 0.0246 AC: 3739 AN: 151906 Hom.: 58 Cov.: 33 AF XY: 0.0244 AC XY: 1815 AN XY: 74254

African (AFR) AF: 0.0135 AC: 558 AN: 41392

American (AMR) AF: 0.0315 AC: 482 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 74 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00788 AC: 38 AN: 4820

European-Finnish (FIN) AF: 0.0272 AC: 287 AN: 10550

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0325 AC: 2210 AN: 67926

Other (OTH) AF: 0.0299 AC: 63 AN: 2108

Alfa AF: 0.0287 Hom.: 22

Bravo AF: 0.0249

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epidermodysplasia verruciformis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.7
DANN	Benign	0.91
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: 2

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

Other links and lift over

dbSNP: rs143140501; hg19: chr17-76113872;