rs117553598

chr17-78120836-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127198.5(TMC6):c.1536-4G>A variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001680
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -9.07

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 -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.1536-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.1536-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 410 AN: 152124 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.00333 AC: 830 AN: 249246 Hom.: 0 AF XY: 0.00346 AC XY: 467 AN XY: 135016

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 SAS exome AF: 0.00399

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.: 15 Cov.: 32 AF XY: 0.00420 AC XY: 3045 AN XY: 725706

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00411

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00446

Gnomad4 OTH exome AF: 0.00483

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152242 Hom.: 2 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74434

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00424 Hom.: 0

Bravo AF: 0.00295

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00433

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	TMC6: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

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

Other links and lift over

dbSNP: rs117553598; hg19: chr17-76116917;