17-78130995-G-T

Variant names:

• chr17-78130995-G-T
• rs11658760
• NM_152468.5:c.-309+144G>T

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.-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
• Publications: 8 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=-0.85).
• 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 rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.-309+144G>T		intron_variant	Intron 1 of 15	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.-309+144G>T		intron_variant	Intron 1 of 15	1	NM_152468.5	ENSP00000325561.4

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

African (AFR) AF: 0.0667 AC: 4 AN: 60

American (AMR) AF: 0.268 AC: 557 AN: 2080

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 139 AN: 294

East Asian (EAS) AF: 0.141 AC: 35 AN: 248

South Asian (SAS) AF: 0.338 AC: 1238 AN: 3668

European-Finnish (FIN) AF: 0.436 AC: 301 AN: 690

Middle Eastern (MID) AF: 0.355 AC: 22 AN: 62

European-Non Finnish (NFE) AF: 0.428 AC: 4646 AN: 10864

Other (OTH) AF: 0.408 AC: 384 AN: 942

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

African (AFR) AF: 0.140 AC: 5823 AN: 41490

American (AMR) AF: 0.311 AC: 4750 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1640 AN: 3470

East Asian (EAS) AF: 0.196 AC: 1014 AN: 5166

South Asian (SAS) AF: 0.374 AC: 1804 AN: 4826

European-Finnish (FIN) AF: 0.488 AC: 5173 AN: 10594

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.477 AC: 32389 AN: 67936

Other (OTH) AF: 0.363 AC: 765 AN: 2106

Alfa AF: 0.360 Hom.: 7544

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

-

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	-0.85
CADD	Benign	4.1
DANN	Benign	0.55
PhyloP100		0.20
PromoterAI		-0.040	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11658760; hg19: chr17-76127076;