rs11658760

Positions:

• chr17-78130995-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152468.5(TMC8):​c.-309+144G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 170,992 control chromosomes in the GnomAD database, including 12,871 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11192 hom., cov: 32)
  • Exomes 𝑓: 0.39 (1679 hom.)
• Consequence: TMC8 NM_152468.5 intron
• Scores: Splicing: ADA: 0.00004195
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.197

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]

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=-0.85).
• BP6: Variant 17-78130995-G-T is Benign according to our data. Variant chr17-78130995-G-T is described in ClinVar as [Benign]. Clinvar id is 1228172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5	c.-309+144G>T		intron_variant		ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.-309+144G>T		intron_variant		1	NM_152468.5	P2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53852 AN: 151966 Hom.: 11197 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.311

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.369

GnomAD4 exome AF: 0.387 AC: 7326 AN: 18908 Hom.: 1679 Cov.: 0 AF XY: 0.373 AC XY: 3774 AN XY: 10112

Gnomad4 AFR exome AF: 0.0667

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.338

Gnomad4 FIN exome AF: 0.436

Gnomad4 NFE exome AF: 0.428

Gnomad4 OTH exome AF: 0.408

GnomAD4 genome AF: 0.354 AC: 53845 AN: 152084 Hom.: 11192 Cov.: 32 AF XY: 0.354 AC XY: 26299 AN XY: 74344

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.311

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.374

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.477

Gnomad4 OTH AF: 0.363

Alfa AF: 0.431 Hom.: 3569

Bravo AF: 0.329

Asia WGS AF: 0.251 AC: 875 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.1
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs11658760; hg19: chr17-76127076;