dbSNP rs17773842: TMC8:c.1902+81G>A (chr17-78139321-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152468.5(TMC8):c.1902+81G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,516,928 control chromosomes in the GnomAD database, including 69,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 5019 hom., cov: 33)

Exomes 𝑓: 0.30 ( 64627 hom. )

Consequence

TMC8
NM_152468.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.35

Variant links:

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]

TMC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 17-78139321-G-A is Benign according to our data. Variant chr17-78139321-G-A is described in ClinVar as [Benign]. Clinvar id is 1238978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5 link	c.1902+81G>A		intron_variant	Intron 15 of 15	ENST00000318430.10	NP_689681.2	Q8IU68-1A0A024R8N8B3KXZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10 link	c.1902+81G>A		intron_variant	Intron 15 of 15	1	NM_152468.5	ENSP00000325561.4		Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

34112

AN:

152046

Hom.:

5022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0562

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.338

Gnomad EAS

AF:

0.0171

Gnomad SAS

AF:

0.207

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.344

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.250

GnomAD4 exome

AF:

0.298

AC:

406963

AN:

1364764

Hom.:

64627

AF XY:

0.298

AC XY:

203272

AN XY:

682356

show subpopulations

Gnomad4 AFR exome

AF:

0.0508

Gnomad4 AMR exome

AF:

0.157

Gnomad4 ASJ exome

AF:

0.345

Gnomad4 EAS exome

AF:

0.0115

Gnomad4 SAS exome

AF:

0.221

Gnomad4 FIN exome

AF:

0.298

Gnomad4 NFE exome

AF:

0.328

Gnomad4 OTH exome

AF:

0.285

GnomAD4 genome

AF:

0.224

AC:

34095

AN:

152164

Hom.:

5019

Cov.:

AF XY:

0.220

AC XY:

16400

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0560

Gnomad4 AMR

AF:

0.216

Gnomad4 ASJ

AF:

0.338

Gnomad4 EAS

AF:

0.0170

Gnomad4 SAS

AF:

0.206

Gnomad4 FIN

AF:

0.289

Gnomad4 NFE

AF:

0.328

Gnomad4 OTH

AF:

0.248

Alfa

AF:

0.299

Hom.:

3444

Bravo

AF:

0.212

Asia WGS

AF:

0.112

AC:

393

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.7

DANN

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over