rs16970849

Variant names:

• chr17-78137827-G-A
• rs16970849
• NM_152468.5:c.1349+13G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-78137827-G-A
• chr17-78137827-G-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.1349+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 1,612,106 control chromosomes in the GnomAD database, including 7,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1506 hom., cov: 33)
  • Exomes 𝑓: 0.061 (5912 hom.)
• Consequence: TMC8 NM_152468.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.98
• Publications: 10 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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 (BayesDel_noAF=-0.81).
• BP6: Variant 17-78137827-G-A is Benign according to our data. Variant chr17-78137827-G-A is described in ClinVar as Benign. ClinVar VariationId is 1167028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.219 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	NM_152468.5	MANE Select	c.1349+13G>A		intron	N/A	NP_689681.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	ENST00000318430.10	TSL:1 MANE Select	c.1349+13G>A		intron	N/A	ENSP00000325561.4
	TMC8	ENST00000589691.1	TSL:1	c.680+13G>A		intron	N/A	ENSP00000467482.1
	TMC8	ENST00000590184.2	TSL:4	n.1017+13G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17211 AN: 152166 Hom.: 1494 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.0559

Gnomad FIN AF: 0.0906

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0965

GnomAD2 exomes AF: 0.114 AC: 28334 AN: 248864 AF XY: 0.0983

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.350

Gnomad ASJ exome AF: 0.0489

Gnomad EAS exome AF: 0.194

Gnomad FIN exome AF: 0.0849

Gnomad NFE exome AF: 0.0454

Gnomad OTH exome AF: 0.0889

GnomAD4 exome AF: 0.0613 AC: 89483 AN: 1459822 Hom.: 5912 Cov.: 32 AF XY: 0.0593 AC XY: 43041 AN XY: 726256

African (AFR) AF: 0.204 AC: 6830 AN: 33474

American (AMR) AF: 0.335 AC: 14985 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0497 AC: 1299 AN: 26132

East Asian (EAS) AF: 0.214 AC: 8514 AN: 39700

South Asian (SAS) AF: 0.0509 AC: 4391 AN: 86246

European-Finnish (FIN) AF: 0.0841 AC: 4359 AN: 51824

Middle Eastern (MID) AF: 0.0523 AC: 297 AN: 5674

European-Non Finnish (NFE) AF: 0.0402 AC: 44650 AN: 1111736

Other (OTH) AF: 0.0689 AC: 4158 AN: 60348

GnomAD4 genome AF: 0.113 AC: 17267 AN: 152284 Hom.: 1506 Cov.: 33 AF XY: 0.118 AC XY: 8792 AN XY: 74454

African (AFR) AF: 0.196 AC: 8128 AN: 41540

American (AMR) AF: 0.225 AC: 3442 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3470

East Asian (EAS) AF: 0.195 AC: 1009 AN: 5186

South Asian (SAS) AF: 0.0557 AC: 269 AN: 4830

European-Finnish (FIN) AF: 0.0906 AC: 963 AN: 10628

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0450 AC: 3061 AN: 68016

Other (OTH) AF: 0.0978 AC: 207 AN: 2116

Alfa AF: 0.0653 Hom.: 172

Bravo AF: 0.130

Asia WGS AF: 0.133 AC: 463 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epidermodysplasia verruciformis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16970849; hg19: chr17-76133908; COSMIC: COSV59211985; COSMIC: COSV59211985;