rs748499539

Variant names:

• chr17-78131623-C-A
• rs748499539
• NM_152468.5:c.35C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-78131623-C-A
• chr17-78131623-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152468.5(TMC8):​c.35C>A​(p.Ala12Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A12T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMC8 NM_152468.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.943
• Publications: 0 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]

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]

TMC6 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermodysplasia verruciformis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10952243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5	c.35C>A	p.Ala12Asp	missense_variant	Exon 2 of 16	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10	c.35C>A	p.Ala12Asp	missense_variant	Exon 2 of 16	1	NM_152468.5	ENSP00000325561.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399088 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 690486

African (AFR) AF: 0.00 AC: 0 AN: 31856

American (AMR) AF: 0.00 AC: 0 AN: 36052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 36136

South Asian (SAS) AF: 0.00 AC: 0 AN: 79442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4962

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1080890

Other (OTH) AF: 0.00 AC: 0 AN: 57986

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	2.0
DANN	Benign	0.76
DEOGEN2	Benign	0.0083	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	.;M
PhyloP100		-0.94
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.22
Sift	Uncertain	0.0090	.;D
Sift4G	Uncertain	0.028	D;D
Polyphen		0.093	.;B
Vest4		0.090
MutPred		0.14		Loss of MoRF binding (P = 0.0697);Loss of MoRF binding (P = 0.0697);
MVP		0.16
MPC		1.5
ClinPred		0.22	T
GERP RS		0.074
Varity_R		0.12
gMVP		0.59
Mutation Taster		=91/9	polymorphism

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: rs748499539; hg19: chr17-76127704;