rs34712518

Variant names:

• chr17-78124950-C-T
• rs34712518
• NM_001127198.5:c.572G>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.572G>A​(p.Gly191Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,598,844 control chromosomes in the GnomAD database, including 4,431 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (860 hom., cov: 34)
  • Exomes 𝑓: 0.067 (3571 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.62
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011823177).
• BP6: Variant 17-78124950-C-T is Benign according to our data. Variant chr17-78124950-C-T is described in ClinVar as Benign. ClinVar VariationId is 1164814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

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.572G>A	p.Gly191Asp	missense	Exon 7 of 20	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.572G>A	p.Gly191Asp	missense	Exon 7 of 20	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.572G>A	p.Gly191Asp	missense	Exon 7 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.572G>A	p.Gly191Asp	missense	Exon 7 of 20	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.572G>A	p.Gly191Asp	missense	Exon 7 of 20	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.572G>A	p.Gly191Asp	missense	Exon 6 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14074 AN: 152196 Hom.: 857 Cov.: 34

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.0615

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0833

GnomAD2 exomes AF: 0.0657 AC: 14267 AN: 217266 AF XY: 0.0644

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0304

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.0923

Gnomad FIN exome AF: 0.0592

Gnomad NFE exome AF: 0.0600

Gnomad OTH exome AF: 0.0617

GnomAD4 exome AF: 0.0671 AC: 96994 AN: 1446530 Hom.: 3571 Cov.: 34 AF XY: 0.0660 AC XY: 47465 AN XY: 718814

African (AFR) AF: 0.177 AC: 5906 AN: 33288

American (AMR) AF: 0.0329 AC: 1428 AN: 43366

Ashkenazi Jewish (ASJ) AF: 0.0942 AC: 2436 AN: 25868

East Asian (EAS) AF: 0.0850 AC: 3339 AN: 39270

South Asian (SAS) AF: 0.0540 AC: 4574 AN: 84724

European-Finnish (FIN) AF: 0.0547 AC: 2610 AN: 47718

Middle Eastern (MID) AF: 0.0401 AC: 220 AN: 5492

European-Non Finnish (NFE) AF: 0.0652 AC: 72217 AN: 1107054

Other (OTH) AF: 0.0714 AC: 4264 AN: 59750

GnomAD4 genome AF: 0.0925 AC: 14082 AN: 152314 Hom.: 860 Cov.: 34 AF XY: 0.0924 AC XY: 6882 AN XY: 74472

African (AFR) AF: 0.174 AC: 7219 AN: 41566

American (AMR) AF: 0.0484 AC: 741 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3472

East Asian (EAS) AF: 0.0961 AC: 498 AN: 5180

South Asian (SAS) AF: 0.0561 AC: 271 AN: 4828

European-Finnish (FIN) AF: 0.0615 AC: 653 AN: 10622

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0606 AC: 4119 AN: 68022

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.0707 Hom.: 364

Bravo AF: 0.0945

TwinsUK AF: 0.0650 AC: 241

ALSPAC AF: 0.0672 AC: 259

ESP6500AA AF: 0.152 AC: 664

ESP6500EA AF: 0.0613 AC: 524

ExAC AF: 0.0623 AC: 7481

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.58
DANN	Benign	0.86
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-2.6
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.032
Sift	Benign	0.71	T
Sift4G	Benign	0.23	T
Polyphen		0.0080	B
Vest4		0.044
MPC		0.21
ClinPred		0.0087	T
GERP RS		-5.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.072
gMVP		0.31
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34712518; hg19: chr17-76121031; COSMIC: COSV59808094; COSMIC: COSV59808094;