17-78131350-G-C

Position:

• chr17-78131350-G-C

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.-239G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 603,386 control chromosomes in the GnomAD database, including 164,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43085 hom., cov: 32)
  • Exomes 𝑓: 0.73 (121586 hom.)
• Consequence: TMC8 NM_152468.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21

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=-0.93).
• BP6: Variant 17-78131350-G-C is Benign according to our data. Variant chr17-78131350-G-C is described in ClinVar as [Benign]. Clinvar id is 1261052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5	c.-239G>C		5_prime_UTR_variant	2/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.-239G>C		5_prime_UTR_variant	2/16	1	NM_152468.5	P2

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113634 AN: 151964 Hom.: 43047 Cov.: 32

Gnomad AFR AF: 0.809

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.834

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.738

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.759

Gnomad OTH AF: 0.760

GnomAD4 exome AF: 0.727 AC: 328311 AN: 451304 Hom.: 121586 Cov.: 5 AF XY: 0.728 AC XY: 173343 AN XY: 238128

Gnomad4 AFR exome AF: 0.811

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.830

Gnomad4 EAS exome AF: 0.434

Gnomad4 SAS exome AF: 0.721

Gnomad4 FIN exome AF: 0.740

Gnomad4 NFE exome AF: 0.761

Gnomad4 OTH exome AF: 0.745

GnomAD4 genome AF: 0.748 AC: 113727 AN: 152082 Hom.: 43085 Cov.: 32 AF XY: 0.744 AC XY: 55303 AN XY: 74344

Gnomad4 AFR AF: 0.809

Gnomad4 AMR AF: 0.620

Gnomad4 ASJ AF: 0.834

Gnomad4 EAS AF: 0.491

Gnomad4 SAS AF: 0.726

Gnomad4 FIN AF: 0.738

Gnomad4 NFE AF: 0.759

Gnomad4 OTH AF: 0.759

Alfa AF: 0.670 Hom.: 1965

Bravo AF: 0.737

Asia WGS AF: 0.611 AC: 2125 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	-0.93
CADD	Benign	2.0
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs383603; hg19: chr17-76127431;