chr17-78131665-T-C

Position:

• chr17-78131665-T-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.77T>C​(p.Met26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,568,410 control chromosomes in the GnomAD database, including 1,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (82 hom., cov: 34)
  • Exomes 𝑓: 0.032 (931 hom.)
• Consequence: TMC8 NM_152468.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.165

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 (MetaRNN=0.0019472837).
• BP6: Variant 17-78131665-T-C is Benign according to our data. Variant chr17-78131665-T-C is described in ClinVar as [Benign]. Clinvar id is 1169102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78131665-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5	c.77T>C	p.Met26Thr	missense_variant	2/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.77T>C	p.Met26Thr	missense_variant	2/16	1	NM_152468.5	P2
TMC6	ENST00000322914.7	c.-75+676A>G		intron_variant		1		P1
TMC8	ENST00000589691.1	c.-372+260T>C		intron_variant		1		A2
TMC8	ENST00000590799.5	n.459T>C		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3630 AN: 152218 Hom.: 83 Cov.: 34

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0330

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0819

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0321 AC: 5477 AN: 170648 Hom.: 155 AF XY: 0.0353 AC XY: 3258 AN XY: 92302

Gnomad AFR exome AF: 0.00378

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.00669

Gnomad SAS exome AF: 0.0777

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0312

Gnomad OTH exome AF: 0.0363

GnomAD4 exome AF: 0.0324 AC: 45814 AN: 1416076 Hom.: 931 Cov.: 32 AF XY: 0.0339 AC XY: 23745 AN XY: 700296

Gnomad4 AFR exome AF: 0.00583

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.0386

Gnomad4 EAS exome AF: 0.00294

Gnomad4 SAS exome AF: 0.0770

Gnomad4 FIN exome AF: 0.0135

Gnomad4 NFE exome AF: 0.0314

Gnomad4 OTH exome AF: 0.0371

GnomAD4 genome AF: 0.0238 AC: 3628 AN: 152334 Hom.: 82 Cov.: 34 AF XY: 0.0240 AC XY: 1788 AN XY: 74490

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.0329

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.00694

Gnomad4 SAS AF: 0.0814

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.0305

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0281 Hom.: 32

Bravo AF: 0.0234

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.00355 AC: 15

ESP6500EA AF: 0.0261 AC: 218

ExAC AF: 0.0230 AC: 2654

Asia WGS AF: 0.0430 AC: 148 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	- -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.014	.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	.;M
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.2	.;N
REVEL	Benign	0.15
Sift	Benign	0.097	.;T
Sift4G	Uncertain	0.021	D;D
Polyphen		0.0050	.;B
Vest4		0.11
MPC		1.7
ClinPred		0.013	T
GERP RS		3.1
Varity_R		0.17
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs145016347; hg19: chr17-76127746;