rs553985699

chr17-78125743-G-Achr17-78125743-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127198.5(TMC6):c.413C>T(p.Thr138Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000823 in 1,568,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T138T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.988

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026517719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.413C>T	p.Thr138Met	missense_variant	5/20	ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.413C>T	p.Thr138Met	missense_variant	5/20	2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000101 AC: 18 AN: 178490 Hom.: 0 AF XY: 0.0000732 AC XY: 7 AN XY: 95682

Gnomad AFR exome AF: 0.000102

Gnomad AMR exome AF: 0.000252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.000209

GnomAD4 exome AF: 0.0000819 AC: 116 AN: 1415788 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 47 AN XY: 700292

Gnomad4 AFR exome AF: 0.0000623

Gnomad4 AMR exome AF: 0.000257

Gnomad4 ASJ exome AF: 0.0000395

Gnomad4 EAS exome AF: 0.0000273

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000891

Gnomad4 OTH exome AF: 0.0000512

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74512

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000102 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermodysplasia verruciformis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 138 of the TMC6 protein (p.Thr138Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TMC6-related conditions. ClinVar contains an entry for this variant (Variation ID: 565842). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.17
Dann	Benign	0.94
DEOGEN2	Benign	0.020	T;T;T;.;.;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.027	T;T;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	Benign	0.39	T
Sift4G	Uncertain	0.036	D;D;D;D;.;.;.
Polyphen		0.71	P;P;P;P;.;.;.
Vest4		0.16
MutPred		0.26		Loss of glycosylation at T138 (P = 0.111);Loss of glycosylation at T138 (P = 0.111);Loss of glycosylation at T138 (P = 0.111);Loss of glycosylation at T138 (P = 0.111);Loss of glycosylation at T138 (P = 0.111);Loss of glycosylation at T138 (P = 0.111);Loss of glycosylation at T138 (P = 0.111);
MVP		0.014
MPC		0.17
ClinPred		0.038	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.22

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: rs553985699; hg19: chr17-76121824;