rs34712518

chr17-78124950-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.572G>A(p.Gly191Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,598,844 control chromosomes in the GnomAD database, including 4,431 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.092 (860 hom., cov: 34)
  • Exomes 𝑓: 0.067 (3571 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.62

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=0.0011823177).
• BP6: Variant 17-78124950-C-T is Benign according to our data. Variant chr17-78124950-C-T is described in ClinVar as [Benign]. Clinvar id is 1164814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.572G>A	p.Gly191Asp	missense_variant	7/20	ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.572G>A	p.Gly191Asp	missense_variant	7/20	2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14074 AN: 152196 Hom.: 857 Cov.: 34

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.0561

Gnomad FIN AF: 0.0615

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0833

GnomAD3 exomes AF: 0.0657 AC: 14267 AN: 217266 Hom.: 531 AF XY: 0.0644 AC XY: 7689 AN XY: 119430

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0304

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.0923

Gnomad SAS exome AF: 0.0555

Gnomad FIN exome AF: 0.0592

Gnomad NFE exome AF: 0.0600

Gnomad OTH exome AF: 0.0617

GnomAD4 exome AF: 0.0671 AC: 96994 AN: 1446530 Hom.: 3571 Cov.: 34 AF XY: 0.0660 AC XY: 47465 AN XY: 718814

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.0329

Gnomad4 ASJ exome AF: 0.0942

Gnomad4 EAS exome AF: 0.0850

Gnomad4 SAS exome AF: 0.0540

Gnomad4 FIN exome AF: 0.0547

Gnomad4 NFE exome AF: 0.0652

Gnomad4 OTH exome AF: 0.0714

GnomAD4 genome AF: 0.0925 AC: 14082 AN: 152314 Hom.: 860 Cov.: 34 AF XY: 0.0924 AC XY: 6882 AN XY: 74472

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.0484

Gnomad4 ASJ AF: 0.0988

Gnomad4 EAS AF: 0.0961

Gnomad4 SAS AF: 0.0561

Gnomad4 FIN AF: 0.0615

Gnomad4 NFE AF: 0.0606

Gnomad4 OTH AF: 0.0819

Alfa AF: 0.0698 Hom.: 337

Bravo AF: 0.0945

TwinsUK AF: 0.0650 AC: 241

ALSPAC AF: 0.0672 AC: 259

ESP6500AA AF: 0.152 AC: 664

ESP6500EA AF: 0.0613 AC: 524

ExAC AF: 0.0623 AC: 7481

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.58
Dann	Benign	0.86
DEOGEN2	Benign	0.020	T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.098	N
MetaRNN	Benign	0.0012	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M;M;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.23	T;T;T;T;.
Polyphen		0.0080	B;B;B;B;.
Vest4		0.044
MPC		0.21
ClinPred		0.0087	T
GERP RS		-5.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.072
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs34712518; hg19: chr17-76121031; COSMIC: COSV59808094; COSMIC: COSV59808094;