Genetic Variant NM_152468.5:c.1128-624T>C (chr17-78136611-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_152468.5(TMC8):c.1128-624T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 172,348 control chromosomes in the GnomAD database, including 3,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.19 ( 2765 hom., cov: 33)

Exomes 𝑓: 0.17 ( 368 hom. )

Consequence

TMC8
NM_152468.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.812

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

epidermodysplasia verruciformis, susceptibility to, 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
epidermodysplasia verruciformis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 17-78136611-T-C is Benign according to our data. Variant chr17-78136611-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688349.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5 link	c.1128-624T>C		intron_variant	Intron 9 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.1128-624T>C		intron_variant	Intron 9 of 15	1	NM_152468.5	ENSP00000325561.4		Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28322

AN:

152082

Hom.:

2757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.294

Gnomad AMR

AF:

0.162

Gnomad ASJ

AF:

0.285

Gnomad EAS

AF:

0.224

Gnomad SAS

AF:

0.285

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.184

Gnomad OTH

AF:

0.213

GnomAD4 exome

AF:

0.169

AC:

3411

AN:

20148

Hom.:

368

Cov.:

AF XY:

0.180

AC XY:

1940

AN XY:

10778

show subpopulations

African (AFR)

AF:

0.126

AC:

AN:

286

American (AMR)

AF:

0.147

AC:

457

AN:

3108

Ashkenazi Jewish (ASJ)

AF:

0.179

AC:

AN:

224

East Asian (EAS)

AF:

0.166

AC:

202

AN:

1218

South Asian (SAS)

AF:

0.255

AC:

936

AN:

3672

European-Finnish (FIN)

AF:

0.110

AC:

AN:

374

Middle Eastern (MID)

AF:

0.262

AC:

AN:

European-Non Finnish (NFE)

AF:

0.149

AC:

1543

AN:

10364

Other (OTH)

AF:

0.169

AC:

145

AN:

860

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

133

266

400

533

666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.186

AC:

28362

AN:

152200

Hom.:

2765

Cov.:

AF XY:

0.190

AC XY:

14126

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.162

AC:

6725

AN:

41512

American (AMR)

AF:

0.162

AC:

2482

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

987

AN:

3468

East Asian (EAS)

AF:

0.224

AC:

1161

AN:

5190

South Asian (SAS)

AF:

0.286

AC:

1382

AN:

4824

European-Finnish (FIN)

AF:

0.216

AC:

2289

AN:

10588

Middle Eastern (MID)

AF:

0.333

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.184

AC:

12508

AN:

67994

Other (OTH)

AF:

0.218

AC:

462

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1236

2471

3707

4942

6178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.189

Hom.:

7123

Bravo

AF:

0.179

Asia WGS

AF:

0.267

AC:

927

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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 20% of patients studied by a panel of primary immunodeficiencies. Number of patients: 19. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.39

(source)

DANN

Benign

0.34

PhyloP100

-0.81

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over