17-78131350-G-C

Variant names:

• chr17-78131350-G-C
• rs383603
• NM_152468.5:c.-239G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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]

TMC6 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermodysplasia verruciformis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.-239G>C		5_prime_UTR_variant	Exon 2 of 16	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.-239G>C		5_prime_UTR_variant	Exon 2 of 16	1	NM_152468.5	ENSP00000325561.4

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

African (AFR) AF: 0.811 AC: 9866 AN: 12166

American (AMR) AF: 0.537 AC: 9944 AN: 18514

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 11112 AN: 13386

East Asian (EAS) AF: 0.434 AC: 13079 AN: 30156

South Asian (SAS) AF: 0.721 AC: 33321 AN: 46222

European-Finnish (FIN) AF: 0.740 AC: 20667 AN: 27932

Middle Eastern (MID) AF: 0.807 AC: 1584 AN: 1962

European-Non Finnish (NFE) AF: 0.761 AC: 209537 AN: 275208

Other (OTH) AF: 0.745 AC: 19201 AN: 25758

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

African (AFR) AF: 0.809 AC: 33545 AN: 41478

American (AMR) AF: 0.620 AC: 9469 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 2897 AN: 3472

East Asian (EAS) AF: 0.491 AC: 2538 AN: 5164

South Asian (SAS) AF: 0.726 AC: 3500 AN: 4824

European-Finnish (FIN) AF: 0.738 AC: 7824 AN: 10596

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.759 AC: 51571 AN: 67954

Other (OTH) AF: 0.759 AC: 1602 AN: 2110

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

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	-0.93
CADD	Benign	2.0
DANN	Benign	0.50
PhyloP100		-1.2
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs383603; hg19: chr17-76127431;