17-78122693-G-T

Variant names:

• chr17-78122693-G-T
• rs147856997
• NM_001127198.5:c.1139C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001127198.5(TMC6):​c.1139C>A​(p.Ala380Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A380T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.96
• Publications: 2 publications found

Genes affected

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: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• epidermodysplasia verruciformis

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127198.5. 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
	TMC6	NM_001127198.5	MANE Select	c.1139C>A	p.Ala380Asp	missense	Exon 10 of 20	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.1139C>A	p.Ala380Asp	missense	Exon 10 of 20	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.1139C>A	p.Ala380Asp	missense	Exon 10 of 20	NP_001361525.1	Q7Z403-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	ENST00000590602.6	TSL:2 MANE Select	c.1139C>A	p.Ala380Asp	missense	Exon 10 of 20	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.1139C>A	p.Ala380Asp	missense	Exon 10 of 20	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.1139C>A	p.Ala380Asp	missense	Exon 9 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246162 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459408 Hom.: 0 Cov.: 31 AF XY: 0.00000689 AC XY: 5 AN XY: 725872

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111410

Other (OTH) AF: 0.0000166 AC: 1 AN: 60282

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.86
MutPred		0.61		Gain of sheet (P = 0.0477)
MVP		0.58
MPC		0.82
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.87
Mutation Taster		=64/36	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: rs147856997; hg19: chr17-76118774;