rs75400929

chr17-78121043-G-Achr17-78121043-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127198.5(TMC6):c.1505C>T(p.Pro502Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00827 in 1,613,348 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P502P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (105 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.46

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=0.0065681934).
• BP6: Variant 17-78121043-G-A is Benign according to our data. Variant chr17-78121043-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 456008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78121043-G-A is described in Lovd as [Likely_benign]. Variant chr17-78121043-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00724 (1102/152300) while in subpopulation NFE AF= 0.00906 (616/68012). AF 95% confidence interval is 0.00847. There are 15 homozygotes in gnomad4. There are 600 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.1505C>T	p.Pro502Leu	missense_variant	12/20	ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.1505C>T	p.Pro502Leu	missense_variant	12/20	2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1102 AN: 152182 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00906

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00849 AC: 2126 AN: 250436 Hom.: 16 AF XY: 0.00807 AC XY: 1095 AN XY: 135688

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.00976

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00838 AC: 12247 AN: 1461048 Hom.: 105 Cov.: 32 AF XY: 0.00803 AC XY: 5838 AN XY: 726844

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00217

Gnomad4 FIN exome AF: 0.0390

Gnomad4 NFE exome AF: 0.00853

Gnomad4 OTH exome AF: 0.00672

GnomAD4 genome AF: 0.00724 AC: 1102 AN: 152300 Hom.: 15 Cov.: 32 AF XY: 0.00806 AC XY: 600 AN XY: 74470

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0371

Gnomad4 NFE AF: 0.00906

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00764 Hom.: 12

Bravo AF: 0.00447

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00858 AC: 1042

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

TMC6: BS2 -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0066	T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.9	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.39
MVP		0.69
MPC		0.68
ClinPred		0.053	T
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.79
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs75400929; hg19: chr17-76117124; COSMIC: COSV59809884; COSMIC: COSV59809884;