rs62079073

Positions:

• chr17-78134866-G-A
• chr17-78134866-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152468.5(TMC8):​c.988-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000739 in 1,613,710 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: TMC8 NM_152468.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003614
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -1.18

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-78134866-G-A is Benign according to our data. Variant chr17-78134866-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 526264.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-78134866-G-A is described in Lovd as [Benign]. Variant chr17-78134866-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000716 (109/152190) while in subpopulation AFR AF= 0.00108 (45/41516). AF 95% confidence interval is 0.000832. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC8	NM_152468.5	c.988-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.988-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_152468.5	ENSP00000325561	P2

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000622 AC: 156 AN: 250726 Hom.: 1 AF XY: 0.000722 AC XY: 98 AN XY: 135684

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.000874

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000741 AC: 1083 AN: 1461520 Hom.: 2 Cov.: 34 AF XY: 0.000744 AC XY: 541 AN XY: 727060

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.000358

Gnomad4 NFE exome AF: 0.000807

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74426

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000780

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000237 Hom.: 167

EpiCase AF: 0.000818

EpiControl AF: 0.000949

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Epidermodysplasia verruciformis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.28
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.15		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: rs62079073; hg19: chr17-76130947;