17-78134494-A-T

Variant names:

• chr17-78134494-A-T
• rs7208422
• NM_152468.5:c.917A>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.917A>T​(p.Asn306Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,692 control chromosomes in the GnomAD database, including 202,590 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N306N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.55 (23584 hom., cov: 32)
  • Exomes 𝑓: 0.49 (179006 hom.)
• Consequence: TMC8 NM_152468.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.971
• Publications: 62 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]

TMC8 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• epidermodysplasia verruciformis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.422793E-6).
• BP6: Variant 17-78134494-A-T is Benign according to our data. Variant chr17-78134494-A-T is described in ClinVar as Benign. ClinVar VariationId is 403548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152468.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	NM_152468.5	MANE Select	c.917A>T	p.Asn306Ile	missense	Exon 8 of 16	NP_689681.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	ENST00000318430.10	TSL:1 MANE Select	c.917A>T	p.Asn306Ile	missense	Exon 8 of 16	ENSP00000325561.4	Q8IU68-1
	TMC8	ENST00000589691.1	TSL:1	c.248A>T	p.Asn83Ile	missense	Exon 7 of 15	ENSP00000467482.1	Q8IU68-2
	TMC8	ENST00000972441.1		c.917A>T	p.Asn306Ile	missense	Exon 8 of 16	ENSP00000642500.1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83414 AN: 151862 Hom.: 23541 Cov.: 32

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.537

GnomAD2 exomes AF: 0.512 AC: 128377 AN: 250684 AF XY: 0.508

Gnomad AFR exome AF: 0.683

Gnomad AMR exome AF: 0.562

Gnomad ASJ exome AF: 0.537

Gnomad EAS exome AF: 0.427

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.495

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.493 AC: 720199 AN: 1461712 Hom.: 179006 Cov.: 70 AF XY: 0.493 AC XY: 358325 AN XY: 727136

African (AFR) AF: 0.686 AC: 22967 AN: 33480

American (AMR) AF: 0.561 AC: 25064 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 14012 AN: 26136

East Asian (EAS) AF: 0.464 AC: 18423 AN: 39700

South Asian (SAS) AF: 0.493 AC: 42526 AN: 86256

European-Finnish (FIN) AF: 0.483 AC: 25758 AN: 53286

Middle Eastern (MID) AF: 0.573 AC: 3303 AN: 5768

European-Non Finnish (NFE) AF: 0.483 AC: 537173 AN: 1111974

Other (OTH) AF: 0.513 AC: 30973 AN: 60396

GnomAD4 genome AF: 0.550 AC: 83516 AN: 151980 Hom.: 23584 Cov.: 32 AF XY: 0.550 AC XY: 40835 AN XY: 74274

African (AFR) AF: 0.677 AC: 28061 AN: 41430

American (AMR) AF: 0.576 AC: 8805 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1870 AN: 3472

East Asian (EAS) AF: 0.432 AC: 2220 AN: 5144

South Asian (SAS) AF: 0.507 AC: 2444 AN: 4820

European-Finnish (FIN) AF: 0.484 AC: 5113 AN: 10570

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33301 AN: 67954

Other (OTH) AF: 0.541 AC: 1141 AN: 2110

Alfa AF: 0.510 Hom.: 6487

Bravo AF: 0.561

TwinsUK AF: 0.468 AC: 1736

ALSPAC AF: 0.489 AC: 1883

ESP6500AA AF: 0.686 AC: 3021

ESP6500EA AF: 0.489 AC: 4209

ExAC AF: 0.514 AC: 62416

Asia WGS AF: 0.502 AC: 1747 AN: 3478

EpiCase AF: 0.503

EpiControl AF: 0.513

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (3)
-	-	1	Epidermodysplasia verruciformis (1)
-	-	1	Epidermodysplasia verruciformis, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.3
DANN	Benign	0.79
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0000094	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.6	N
PhyloP100		0.97
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	4.5	N
REVEL	Benign	0.072
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.20
ClinPred		0.0028	T
GERP RS		4.7
Varity_R		0.11
gMVP		0.31
Mutation Taster		=97/3	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: rs7208422; hg19: chr17-76130575; COSMIC: COSV59208605; COSMIC: COSV59208605;