rs147815166

Variant names:

• chr17-78119360-C-T
• rs147815166
• NM_001127198.5:c.1748G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-78119360-C-T
• chr17-78119360-C-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001127198.5(TMC6):​c.1748G>A​(p.Arg583Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R583W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.958
• Publications: 5 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0080060065).
• BP6: Variant 17-78119360-C-T is Benign according to our data. Variant chr17-78119360-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 456009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00137 (209/152286) while in subpopulation AFR AF = 0.00318 (132/41572). AF 95% confidence interval is 0.00273. There are 0 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1748G>A	p.Arg583Gln	missense	Exon 14 of 20	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.1748G>A	p.Arg583Gln	missense	Exon 14 of 20	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.1748G>A	p.Arg583Gln	missense	Exon 14 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.1748G>A	p.Arg583Gln	missense	Exon 14 of 20	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.1748G>A	p.Arg583Gln	missense	Exon 14 of 20	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.1748G>A	p.Arg583Gln	missense	Exon 13 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000517 AC: 130 AN: 251418 AF XY: 0.000464

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00124 AC: 1812 AN: 1461764 Hom.: 0 Cov.: 34 AF XY: 0.00111 AC XY: 809 AN XY: 727170

African (AFR) AF: 0.00260 AC: 87 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00145 AC: 1611 AN: 1112008

Other (OTH) AF: 0.00156 AC: 94 AN: 60392

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74456

African (AFR) AF: 0.00318 AC: 132 AN: 41572

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000967 Hom.: 0

Bravo AF: 0.00130

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.000545

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epidermodysplasia verruciformis (1)
-	-	1	not provided (1)
-	-	1	TMC6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.96
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.033
Sift	Benign	0.59	T
Sift4G	Benign	0.37	T
Polyphen		0.18	B
Vest4		0.18
MVP		0.21
MPC		0.19
ClinPred		0.013	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.15
Mutation Taster		=90/10	polymorphism

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: rs147815166; hg19: chr17-76115441; COSMIC: COSV59809419; COSMIC: COSV59809419;