rs144120533

Positions:

• chr17-78138386-C-T

Variant summary

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

The ENST00000318430.10(TMC8):​c.1571C>T​(p.Pro524Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,611,936 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (11 hom.)
• Consequence: TMC8 ENST00000318430.10 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.503

Genes affected

TMC8 (HGNC:20474): (transmembrane channel like 8) 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 8 predicted transmembrane domains and 3 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=0.015380949).
• BP6: Variant 17-78138386-C-T is Benign according to our data. Variant chr17-78138386-C-T is described in ClinVar as [Benign]. Clinvar id is 456023.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-78138386-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00165 (251/152324) while in subpopulation NFE AF= 0.0031 (211/68016). AF 95% confidence interval is 0.00276. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC8	NM_152468.5	c.1571C>T	p.Pro524Leu	missense_variant	13/16	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.1571C>T	p.Pro524Leu	missense_variant	13/16	1	NM_152468.5	ENSP00000325561	P2

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152206 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00204 AC: 509 AN: 249822 Hom.: 2 AF XY: 0.00200 AC XY: 271 AN XY: 135216

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00253 AC: 3688 AN: 1459612 Hom.: 11 Cov.: 33 AF XY: 0.00254 AC XY: 1841 AN XY: 726202

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00160

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152324 Hom.: 1 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74482

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00252 Hom.: 3

Bravo AF: 0.00147

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.5
DANN	Benign	0.70
DEOGEN2	Benign	0.093	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.075	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.098
Sift	Benign	0.26	T;.
Sift4G	Benign	0.70	T;T
Polyphen		0.0	B;.
Vest4		0.070
MVP		0.39
MPC		0.17
ClinPred		0.0011	T
GERP RS		-2.3
Varity_R		0.064
gMVP		0.17

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: rs144120533; hg19: chr17-76134467;