rs117553598

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127198.5(TMC6):c.1536-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,611,704 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 15 hom. )

Consequence

TMC6
NM_001127198.5 splice_region, intron

Scores

Splicing: ADA: 0.00001680

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -9.07

Variant links:

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]

TMC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

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

BP6

Variant 17-78120836-C-T is Benign according to our data. Variant chr17-78120836-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 526253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78120836-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00269 (410/152242) while in subpopulation NFE AF = 0.00418 (284/68014). AF 95% confidence interval is 0.00378. There are 2 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5 link	c.1536-4G>A		splice_region_variant, intron_variant	Intron 12 of 19	ENST00000590602.6	NP_001120670.1	Q7Z403-1A0A024R8V2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6 link	c.1536-4G>A		splice_region_variant, intron_variant	Intron 12 of 19	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.00270

AC:

410

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000580

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00418

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00333

AC:

830

AN:

249246

AF XY:

0.00346

show subpopulations

Gnomad AFR exome

AF:

0.000807

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000883

Gnomad NFE exome

AF:

0.00387

Gnomad OTH exome

AF:

0.00459

GnomAD4 exome

AF:

0.00427

AC:

6232

AN:

1459462

Hom.:

Cov.:

AF XY:

0.00420

AC XY:

3045

AN XY:

725706

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

AC:

AN:

33460

Gnomad4 AMR exome

AF:

0.00154

AC:

AN:

44704

Gnomad4 ASJ exome

AF:

0.0164

AC:

427

AN:

26098

Gnomad4 EAS exome

AF:

0.000126

AC:

AN:

39674

Gnomad4 SAS exome

AF:

0.00411

AC:

354

AN:

86232

Gnomad4 FIN exome

AF:

0.00112

AC:

AN:

52538

Gnomad4 NFE exome

AF:

0.00446

AC:

4956

AN:

1110692

Gnomad4 Remaining exome

AF:

0.00483

AC:

291

AN:

60302

Heterozygous variant carriers

421

843

1264

1686

2107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

202

404

606

808

1010

<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:

0.00269

AC:

410

AN:

152242

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

190

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000578

AC:

0.000577895

AN:

0.000577895

Gnomad4 AMR

AF:

0.00183

AC:

0.00182983

AN:

0.00182983

Gnomad4 ASJ

AF:

0.0133

AC:

0.0132565

AN:

0.0132565

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00228

AC:

0.00228027

AN:

0.00228027

Gnomad4 FIN

AF:

0.000472

AC:

0.000471787

AN:

0.000471787

Gnomad4 NFE

AF:

0.00418

AC:

0.00417561

AN:

0.00417561

Gnomad4 OTH

AF:

0.00332

AC:

0.00331754

AN:

0.00331754

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<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:

0.00424

Hom.:

Bravo

AF:

0.00295

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00433

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMC6: BP4, BS2 -

Epidermodysplasia verruciformis

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.0070

DANN

Benign

0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0

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

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