rs376851783

chr17-78124785-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_001127198.5(TMC6):c.634-4G>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 0.0000703 in 1,579,732 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: TMC6 NM_001127198.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006419
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.15

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-78124785-C-T is Benign according to our data. Variant chr17-78124785-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 526251.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000309 (47/152338) while in subpopulation AFR AF= 0.00106 (44/41586). AF 95% confidence interval is 0.000809. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.634-4G>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.634-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000114 AC: 21 AN: 184642 Hom.: 0 AF XY: 0.000129 AC XY: 13 AN XY: 100766

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.0000361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000259

Gnomad OTH exome AF: 0.000407

GnomAD4 exome AF: 0.0000448 AC: 64 AN: 1427394 Hom.: 0 Cov.: 33 AF XY: 0.0000509 AC XY: 36 AN XY: 707262

Gnomad4 AFR exome AF: 0.000946

Gnomad4 AMR exome AF: 0.0000512

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000228

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74488

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000321

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermodysplasia verruciformis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.038
Dann	Benign	0.93
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
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: rs376851783; hg19: chr17-76120866;