chr17-78125783-A-G

Variant names:

• chr17-78125783-A-G
• rs2748427
• NM_001127198.5:c.373T>C

Variant summary

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

The NM_007267.7(TMC6):​c.373T>C​(p.Trp125Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,562,906 control chromosomes in the GnomAD database, including 45,052 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (7352 hom., cov: 33)
  • Exomes 𝑓: 0.23 (37700 hom.)
• Consequence: TMC6 NM_007267.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.17
• Publications: 46 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

ENSG00000309534 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014621019).
• BP6: Variant 17-78125783-A-G is Benign according to our data. Variant chr17-78125783-A-G is described in ClinVar as Benign. ClinVar VariationId is 403546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007267.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	NM_001127198.5	MANE Select	c.373T>C	p.Trp125Arg	missense	Exon 5 of 20	NP_001120670.1
	TMC6	NM_001321185.1		c.373T>C	p.Trp125Arg	missense	Exon 5 of 20	NP_001308114.1
	TMC6	NM_001374596.1		c.373T>C	p.Trp125Arg	missense	Exon 5 of 20	NP_001361525.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	ENST00000590602.6	TSL:2 MANE Select	c.373T>C	p.Trp125Arg	missense	Exon 5 of 20	ENSP00000465261.1
	TMC6	ENST00000322914.7	TSL:1	c.373T>C	p.Trp125Arg	missense	Exon 5 of 20	ENSP00000313408.2
	TMC6	ENST00000392467.7	TSL:1	c.373T>C	p.Trp125Arg	missense	Exon 4 of 19	ENSP00000376260.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43730 AN: 151992 Hom.: 7334 Cov.: 33

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.238 AC: 40918 AN: 171670 AF XY: 0.238

Gnomad AFR exome AF: 0.456

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.283

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.226 AC: 318865 AN: 1410794 Hom.: 37700 Cov.: 35 AF XY: 0.227 AC XY: 158234 AN XY: 697286

African (AFR) AF: 0.474 AC: 15184 AN: 32002

American (AMR) AF: 0.189 AC: 7147 AN: 37840

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6153 AN: 25264

East Asian (EAS) AF: 0.227 AC: 8271 AN: 36492

South Asian (SAS) AF: 0.289 AC: 23148 AN: 80136

European-Finnish (FIN) AF: 0.207 AC: 10117 AN: 48944

Middle Eastern (MID) AF: 0.217 AC: 1241 AN: 5716

European-Non Finnish (NFE) AF: 0.215 AC: 233311 AN: 1085982

Other (OTH) AF: 0.245 AC: 14293 AN: 58418

GnomAD4 genome AF: 0.288 AC: 43794 AN: 152112 Hom.: 7352 Cov.: 33 AF XY: 0.287 AC XY: 21360 AN XY: 74374

African (AFR) AF: 0.469 AC: 19444 AN: 41484

American (AMR) AF: 0.221 AC: 3380 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 892 AN: 3470

East Asian (EAS) AF: 0.271 AC: 1401 AN: 5170

South Asian (SAS) AF: 0.306 AC: 1474 AN: 4816

European-Finnish (FIN) AF: 0.209 AC: 2217 AN: 10590

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14232 AN: 67970

Other (OTH) AF: 0.267 AC: 564 AN: 2110

Alfa AF: 0.223 Hom.: 5600

Bravo AF: 0.295

TwinsUK AF: 0.217 AC: 806

ALSPAC AF: 0.221 AC: 852

ESP6500AA AF: 0.426 AC: 1833

ESP6500EA AF: 0.196 AC: 1664

ExAC AF: 0.174 AC: 19670

Asia WGS AF: 0.301 AC: 1043 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Epidermodysplasia verruciformis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.72
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.031	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-2.3	N
PhyloP100		2.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	4.2	N
REVEL	Benign	0.061
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.32		Gain of disorder (P = 6e-04)
MPC		0.28
ClinPred		0.00052	T
GERP RS		4.0
Varity_R		0.062
gMVP		0.51
Mutation Taster		=251/49	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: rs2748427; hg19: chr17-76121864; COSMIC: COSV59807580; COSMIC: COSV59807580;