17-78112992-C-T

Variant names:

• chr17-78112992-C-T
• rs2253277
• NM_001127198.5:c.*156G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127198.5(TMC6):​c.*156G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0734 in 797,506 control chromosomes in the GnomAD database, including 2,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (401 hom., cov: 33)
  • Exomes 𝑓: 0.075 (2176 hom.)
• Consequence: TMC6 NM_001127198.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.144
• Publications: 14 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermodysplasia verruciformis

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-78112992-C-T is Benign according to our data. Variant chr17-78112992-C-T is described in ClinVar as [Benign]. Clinvar id is 1286448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.*156G>A		3_prime_UTR_variant	Exon 20 of 20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.*156G>A		3_prime_UTR_variant	Exon 20 of 20	2	NM_001127198.5	ENSP00000465261.1

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 10035 AN: 152228 Hom.: 400 Cov.: 33

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0721

Gnomad OTH AF: 0.0599

GnomAD4 exome AF: 0.0752 AC: 48514 AN: 645160 Hom.: 2176 Cov.: 8 AF XY: 0.0783 AC XY: 26478 AN XY: 338024

African (AFR) AF: 0.0546 AC: 932 AN: 17084

American (AMR) AF: 0.0404 AC: 1171 AN: 28982

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 686 AN: 17520

East Asian (EAS) AF: 0.146 AC: 4701 AN: 32290

South Asian (SAS) AF: 0.131 AC: 7536 AN: 57658

European-Finnish (FIN) AF: 0.0277 AC: 966 AN: 34830

Middle Eastern (MID) AF: 0.138 AC: 392 AN: 2834

European-Non Finnish (NFE) AF: 0.0704 AC: 29617 AN: 420970

Other (OTH) AF: 0.0762 AC: 2513 AN: 32992

GnomAD4 genome AF: 0.0659 AC: 10033 AN: 152346 Hom.: 401 Cov.: 33 AF XY: 0.0662 AC XY: 4933 AN XY: 74496

African (AFR) AF: 0.0564 AC: 2347 AN: 41584

American (AMR) AF: 0.0538 AC: 823 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.127 AC: 658 AN: 5178

South Asian (SAS) AF: 0.135 AC: 652 AN: 4832

European-Finnish (FIN) AF: 0.0265 AC: 282 AN: 10628

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0721 AC: 4907 AN: 68026

Other (OTH) AF: 0.0583 AC: 123 AN: 2110

Alfa AF: 0.0634 Hom.: 431

Bravo AF: 0.0653

Asia WGS AF: 0.131 AC: 455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.7
DANN	Benign	0.78
PhyloP100		0.14
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2253277; hg19: chr17-76109073; COSMIC: COSV107379833; COSMIC: COSV107379833;