rs139654750

Positions:

• chr17-78124912-G-A
• chr17-78124912-G-C
• chr17-78124912-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001127198.5(TMC6):​c.610C>T​(p.Arg204Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,597,824 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0085 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (17 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.687

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007833868).
• BP6: Variant 17-78124912-G-A is Benign according to our data. Variant chr17-78124912-G-A is described in ClinVar as [Benign]. Clinvar id is 526267.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-78124912-G-A is described in Lovd as [Likely_benign]. Variant chr17-78124912-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00846 (1289/152340) while in subpopulation AFR AF= 0.0283 (1176/41580). AF 95% confidence interval is 0.0269. There are 12 homozygotes in gnomad4. There are 591 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.610C>T	p.Arg204Trp	missense_variant	7/20	ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.610C>T	p.Arg204Trp	missense_variant	7/20	2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.00846 AC: 1288 AN: 152222 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00307

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00253 AC: 541 AN: 213698 Hom.: 5 AF XY: 0.00220 AC XY: 260 AN XY: 118044

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.000420

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.0000634

Gnomad NFE exome AF: 0.000642

Gnomad OTH exome AF: 0.000931

GnomAD4 exome AF: 0.00146 AC: 2108 AN: 1445484 Hom.: 17 Cov.: 33 AF XY: 0.00138 AC XY: 990 AN XY: 718436

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0000775

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.0000209

Gnomad4 NFE exome AF: 0.000709

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.00846 AC: 1289 AN: 152340 Hom.: 12 Cov.: 33 AF XY: 0.00793 AC XY: 591 AN XY: 74494

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.000717 Hom.: 0

Bravo AF: 0.00966

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0186 AC: 81

ESP6500EA AF: 0.000819 AC: 7

ExAC AF: 0.00255 AC: 307

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.75
DEOGEN2	Benign	0.13	T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.089	N
MetaRNN	Benign	0.0078	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.29	T;T;T;T;.
Polyphen		0.0060	B;B;B;B;.
Vest4		0.22
MVP		0.26
MPC		0.17
ClinPred		0.0037	T
GERP RS		-0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139654750; hg19: chr17-76120993; COSMIC: COSV99077240; COSMIC: COSV99077240;