rs201267987

Positions:

• chr17-78124568-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001127198.5(TMC6):​c.847G>A​(p.Gly283Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000727 in 1,612,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.152

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0057682693).
• BP6: Variant 17-78124568-C-T is Benign according to our data. Variant chr17-78124568-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 526266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000486 (74/152304) while in subpopulation NFE AF= 0.000706 (48/68012). AF 95% confidence interval is 0.000547. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.847G>A	p.Gly283Ser	missense_variant	8/20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.847G>A	p.Gly283Ser	missense_variant	8/20	2	NM_001127198.5	ENSP00000465261	P1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000728 AC: 176 AN: 241700 Hom.: 0 AF XY: 0.000798 AC XY: 106 AN XY: 132806

Gnomad AFR exome AF: 0.0000691

Gnomad AMR exome AF: 0.000380

Gnomad ASJ exome AF: 0.00583

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.000916

Gnomad OTH exome AF: 0.000674

GnomAD4 exome AF: 0.000752 AC: 1098 AN: 1459834 Hom.: 0 Cov.: 33 AF XY: 0.000742 AC XY: 539 AN XY: 726216

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.00502

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000193

Gnomad4 NFE exome AF: 0.000753

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000570

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000592 AC: 5

ExAC AF: 0.000679 AC: 82

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00160

ClinVar

Significance: 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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Epidermodysplasia verruciformis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.93
DANN	Benign	0.73
DEOGEN2	Benign	0.0059	T;T;T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.58	.;.;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0058	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.040	.;N;N;N;.;.
REVEL	Benign	0.040
Sift	Benign	0.72	.;T;T;T;.;.
Sift4G	Benign	0.78	T;T;T;T;T;.
Polyphen		0.0020	B;B;B;B;B;.
Vest4		0.20
MVP		0.072
MPC		0.17
ClinPred		0.0092	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.048
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201267987; hg19: chr17-76120649;