rs8078238

Positions:

• chr17-78124556-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127198.5(TMC6):​c.859G>A​(p.Val287Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,611,856 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (58 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (42 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.13

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002837479).
• BP6: Variant 17-78124556-C-T is Benign according to our data. Variant chr17-78124556-C-T is described in ClinVar as [Benign]. Clinvar id is 456018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78124556-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.859G>A	p.Val287Ile	missense_variant	8/20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.859G>A	p.Val287Ile	missense_variant	8/20	2	NM_001127198.5	ENSP00000465261	P1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2359 AN: 152176 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00370 AC: 889 AN: 240366 Hom.: 18 AF XY: 0.00265 AC XY: 350 AN XY: 132298

Gnomad AFR exome AF: 0.0561

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.0000989

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00153

GnomAD4 exome AF: 0.00152 AC: 2215 AN: 1459562 Hom.: 42 Cov.: 33 AF XY: 0.00130 AC XY: 943 AN XY: 726122

Gnomad4 AFR exome AF: 0.0539

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.00330

GnomAD4 genome AF: 0.0155 AC: 2363 AN: 152294 Hom.: 58 Cov.: 33 AF XY: 0.0147 AC XY: 1097 AN XY: 74472

Gnomad4 AFR AF: 0.0546

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00183 Hom.: 2

Bravo AF: 0.0178

ESP6500AA AF: 0.0493 AC: 214

ESP6500EA AF: 0.000238 AC: 2

ExAC AF: 0.00466 AC: 562

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

TMC6-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0020
DANN	Benign	0.77
DEOGEN2	Benign	0.0088	T;T;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.21	.;.;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.11	.;N;N;N;.
REVEL	Benign	0.011
Sift	Benign	0.53	.;T;T;T;.
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.074	B;B;B;B;B
Vest4		0.11
MVP		0.030
MPC		0.13
ClinPred		0.0030	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.012
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8078238; hg19: chr17-76120637; COSMIC: COSV59808961; COSMIC: COSV59808961;