rs12449858

chr17-78125237-G-A

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.457C>T(p.Leu153Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0969 in 1,583,914 control chromosomes in the GnomAD database, including 10,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (1059 hom., cov: 34)
  • Exomes 𝑓: 0.097 (9423 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.37

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=0.0024380684).
• BP6: Variant 17-78125237-G-A is Benign according to our data. Variant chr17-78125237-G-A is described in ClinVar as [Benign]. Clinvar id is 403545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78125237-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.457C>T	p.Leu153Phe	missense_variant	6/20	ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.457C>T	p.Leu153Phe	missense_variant	6/20	2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 14183 AN: 152184 Hom.: 1057 Cov.: 34

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.0432

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0941

Gnomad OTH AF: 0.0933

GnomAD3 exomes AF: 0.133 AC: 26661 AN: 200254 Hom.: 3085 AF XY: 0.121 AC XY: 12996 AN XY: 107504

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.212

Gnomad SAS exome AF: 0.0426

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.0918

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.0973 AC: 139322 AN: 1431612 Hom.: 9423 Cov.: 34 AF XY: 0.0954 AC XY: 67702 AN XY: 709422

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.0457

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.0876

Gnomad4 OTH exome AF: 0.0936

GnomAD4 genome AF: 0.0931 AC: 14186 AN: 152302 Hom.: 1059 Cov.: 34 AF XY: 0.0967 AC XY: 7204 AN XY: 74468

Gnomad4 AFR AF: 0.0261

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.0434

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.0941

Gnomad4 OTH AF: 0.0938

Alfa AF: 0.102 Hom.: 1159

Bravo AF: 0.104

TwinsUK AF: 0.0852 AC: 316

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.0257 AC: 113

ESP6500EA AF: 0.0939 AC: 806

ExAC AF: 0.102 AC: 12256

Asia WGS AF: 0.124 AC: 431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

This variant is associated with the following publications: (PMID: 25854761) -

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	Uncertain	0.36
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T;.;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;.;.
MutationTaster	Benign	0.17	P;P;P;P;P;P
PrimateAI	Uncertain	0.68	T
Sift4G	Uncertain	0.013	D;D;D;D;.;.
Polyphen		0.98	D;D;D;D;.;.
Vest4		0.12
MPC		0.66
ClinPred		0.026	T
GERP RS		3.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.36
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12449858; hg19: chr17-76121318; COSMIC: COSV59809006; COSMIC: COSV59809006;