rs3813026

Variant names:

• chr17-78127447-A-G
• rs3813026
• NM_001127198.5:c.-74-541T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001127198.5(TMC6):​c.-74-541T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 152,248 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.091 (844 hom., cov: 33)
• Consequence: TMC6 NM_001127198.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.-74-541T>C		intron_variant	Intron 1 of 19	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.-74-541T>C		intron_variant	Intron 1 of 19	2	NM_001127198.5	ENSP00000465261.1

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 13901 AN: 152130 Hom.: 841 Cov.: 33

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0498

Gnomad ASJ AF: 0.0991

Gnomad EAS AF: 0.0476

Gnomad SAS AF: 0.0555

Gnomad FIN AF: 0.0495

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0623

Gnomad OTH AF: 0.0817

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0914 AC: 13913 AN: 152248 Hom.: 844 Cov.: 33 AF XY: 0.0906 AC XY: 6742 AN XY: 74446

African (AFR) AF: 0.176 AC: 7296 AN: 41530

American (AMR) AF: 0.0497 AC: 760 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 344 AN: 3470

East Asian (EAS) AF: 0.0475 AC: 246 AN: 5178

South Asian (SAS) AF: 0.0555 AC: 268 AN: 4828

European-Finnish (FIN) AF: 0.0495 AC: 525 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0623 AC: 4239 AN: 68006

Other (OTH) AF: 0.0803 AC: 170 AN: 2116

Alfa AF: 0.0677 Hom.: 909

Bravo AF: 0.0945

Asia WGS AF: 0.0520 AC: 183 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.6
DANN	Benign	0.70
PhyloP100		-2.0
PromoterAI		-0.057	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3813026; hg19: chr17-76123528;