rs200099536

Variant names:

• chr17-78121089-G-A
• rs200099536
• NM_001127198.5:c.1459C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127198.5(TMC6):​c.1459C>T​(p.Pro487Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,612,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22920886).

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.1459C>T	p.Pro487Ser	missense	Exon 12 of 20	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.1459C>T	p.Pro487Ser	missense	Exon 12 of 20	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.1459C>T	p.Pro487Ser	missense	Exon 12 of 20	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.1459C>T	p.Pro487Ser	missense	Exon 12 of 20	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.1459C>T	p.Pro487Ser	missense	Exon 12 of 20	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.1459C>T	p.Pro487Ser	missense	Exon 11 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000443 AC: 11 AN: 248548 AF XY: 0.0000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000806

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460568 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epidermodysplasia verruciformis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.6
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.30
Sift	Benign	0.12	T
Sift4G	Benign	0.073	T
Polyphen		0.94	P
Vest4		0.32
MVP		0.86
MPC		0.20
ClinPred		0.61	D
GERP RS		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.67
Mutation Taster		=57/43	polymorphism

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: rs200099536; hg19: chr17-76117170;