Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127198.5(TMC6):c.1276G>A(p.Gly426Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,602,770 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 6 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0440

Publications

2 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
epidermodysplasia verruciformis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

TMC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051935017).

BP6

Variant 17-78121663-C-T is Benign according to our data. Variant chr17-78121663-C-T is described in ClinVar as Benign. ClinVar VariationId is 456006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00389 (593/152326) while in subpopulation AFR AF = 0.0134 (558/41566). AF 95% confidence interval is 0.0125. There are 6 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMC6	NM_001127198.5	MANE Select	c.1276G>A	p.Gly426Arg	missense	Exon 11 of 20	NP_001120670.1
TMC6	NM_001321185.1		c.1276G>A	p.Gly426Arg	missense	Exon 11 of 20	NP_001308114.1
TMC6	NM_001374596.1		c.1276G>A	p.Gly426Arg	missense	Exon 11 of 20	NP_001361525.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMC6	ENST00000590602.6	TSL:2 MANE Select	c.1276G>A	p.Gly426Arg	missense	Exon 11 of 20	ENSP00000465261.1
TMC6	ENST00000322914.7	TSL:1	c.1276G>A	p.Gly426Arg	missense	Exon 11 of 20	ENSP00000313408.2
TMC6	ENST00000392467.7	TSL:1	c.1276G>A	p.Gly426Arg	missense	Exon 10 of 19	ENSP00000376260.2

Frequencies

GnomAD3 genomes

AF:

0.00390

AC:

593

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00107

AC:

236

AN:

221002

AF XY:

0.000738

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000557

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000363

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.00109

GnomAD4 exome

AF:

0.000477

AC:

692

AN:

1450444

Hom.:

Cov.:

AF XY:

0.000394

AC XY:

284

AN XY:

721260

show subpopulations

African (AFR)

AF:

0.0136

AC:

454

AN:

33354

American (AMR)

AF:

0.000807

AC:

AN:

43348

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25942

East Asian (EAS)

AF:

0.00

AC:

AN:

39254

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85594

European-Finnish (FIN)

AF:

0.000266

AC:

AN:

48878

Middle Eastern (MID)

AF:

0.00157

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000104

AC:

115

AN:

1108420

Other (OTH)

AF:

0.00105

AC:

AN:

59906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00389

AC:

593

AN:

152326

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

262

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0134

AC:

558

AN:

41566

American (AMR)

AF:

0.00137

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68018

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.00432

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00108

AC:

127

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Epidermodysplasia verruciformis (1)

not specified (1)

TMC6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.5

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0085

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.3

PhyloP100

-0.044

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.0

REVEL

Benign

0.046

Sift

Benign

0.27

Sift4G

Benign

0.79

Polyphen

0.0020

Vest4

0.23

MutPred

0.42

Gain of MoRF binding (P = 0.0238)

MVP

0.40

MPC

0.19

ClinPred

0.0091

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.067

gMVP

0.43

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs61744921

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over