rs12452890

Variant names:

• chr17-78134989-G-A
• rs12452890
• NM_152468.5:c.1107G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-78134989-G-A
• chr17-78134989-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152468.5(TMC8):​c.1107G>A​(p.Glu369Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,613,796 control chromosomes in the GnomAD database, including 220,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26105 hom., cov: 32)
  • Exomes 𝑓: 0.51 (194160 hom.)
• Consequence: TMC8 NM_152468.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.43
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 17-78134989-G-A is Benign according to our data. Variant chr17-78134989-G-A is described in ClinVar as Benign. ClinVar VariationId is 403547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 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.1107G>A	p.Glu369Glu	synonymous	Exon 9 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.1107G>A	p.Glu369Glu	synonymous	Exon 9 of 16	ENSP00000325561.4	Q8IU68-1
	TMC8	ENST00000589691.1	TSL:1	c.438G>A	p.Glu146Glu	synonymous	Exon 8 of 15	ENSP00000467482.1	Q8IU68-2
	TMC8	ENST00000972441.1		c.1152G>A	p.Glu384Glu	synonymous	Exon 9 of 16	ENSP00000642500.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87748 AN: 151936 Hom.: 26056 Cov.: 32

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.573

GnomAD2 exomes AF: 0.536 AC: 134805 AN: 251286 AF XY: 0.528

Gnomad AFR exome AF: 0.700

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.414

Gnomad FIN exome AF: 0.562

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.546

GnomAD4 exome AF: 0.512 AC: 748837 AN: 1461742 Hom.: 194160 Cov.: 61 AF XY: 0.510 AC XY: 371153 AN XY: 727178

African (AFR) AF: 0.708 AC: 23688 AN: 33478

American (AMR) AF: 0.614 AC: 27437 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 16002 AN: 26134

East Asian (EAS) AF: 0.433 AC: 17201 AN: 39700

South Asian (SAS) AF: 0.438 AC: 37761 AN: 86254

European-Finnish (FIN) AF: 0.562 AC: 29975 AN: 53360

Middle Eastern (MID) AF: 0.627 AC: 3613 AN: 5766

European-Non Finnish (NFE) AF: 0.505 AC: 561318 AN: 1111938

Other (OTH) AF: 0.527 AC: 31842 AN: 60394

GnomAD4 genome AF: 0.578 AC: 87860 AN: 152054 Hom.: 26105 Cov.: 32 AF XY: 0.577 AC XY: 42891 AN XY: 74330

African (AFR) AF: 0.698 AC: 28942 AN: 41474

American (AMR) AF: 0.607 AC: 9268 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2104 AN: 3466

East Asian (EAS) AF: 0.414 AC: 2134 AN: 5154

South Asian (SAS) AF: 0.432 AC: 2079 AN: 4818

European-Finnish (FIN) AF: 0.575 AC: 6082 AN: 10572

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35343 AN: 67974

Other (OTH) AF: 0.576 AC: 1216 AN: 2112

Alfa AF: 0.554 Hom.: 38199

Bravo AF: 0.590

Asia WGS AF: 0.462 AC: 1606 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.540

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
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.3
DANN	Benign	0.60
PhyloP100		1.4
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: rs12452890; hg19: chr17-76131070; COSMIC: COSV59208716; COSMIC: COSV59208716;