rs185225783

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001127198.5(TMC6):c.712G>A(p.Gly238Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000375 in 1,598,742 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 1 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0130

Publications

0 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: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04543826).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000339 (49/1446422) while in subpopulation AMR AF = 0.000761 (32/42040). AF 95% confidence interval is 0.000553. There are 1 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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	UniProt
TMC6	NM_001127198.5	MANE Select	c.712G>A	p.Gly238Arg	missense	Exon 8 of 20	NP_001120670.1	Q7Z403-1
TMC6	NM_001321185.1		c.712G>A	p.Gly238Arg	missense	Exon 8 of 20	NP_001308114.1	Q7Z403-1
TMC6	NM_001374596.1		c.712G>A	p.Gly238Arg	missense	Exon 8 of 20	NP_001361525.1	Q7Z403-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMC6	ENST00000590602.6	TSL:2 MANE Select	c.712G>A	p.Gly238Arg	missense	Exon 8 of 20	ENSP00000465261.1	Q7Z403-1
TMC6	ENST00000322914.7	TSL:1	c.712G>A	p.Gly238Arg	missense	Exon 8 of 20	ENSP00000313408.2	Q7Z403-1
TMC6	ENST00000392467.7	TSL:1	c.712G>A	p.Gly238Arg	missense	Exon 7 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000129

AC:

AN:

217092

AF XY:

0.000127

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000339

AC:

AN:

1446422

Hom.:

Cov.:

AF XY:

0.0000348

AC XY:

AN XY:

718268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33176

American (AMR)

AF:

0.000761

AC:

AN:

42040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.00

AC:

AN:

38988

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51176

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0000136

AC:

AN:

1105138

Other (OTH)

AF:

0.00

AC:

AN:

59824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.000588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000299

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000746

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epidermodysplasia verruciformis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.033

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.045

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

2.9

PhyloP100

0.013

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.34

Sift

Uncertain

0.014

Sift4G

Benign

0.23

Polyphen

1.0

Vest4

0.58

MutPred

0.55

Gain of MoRF binding (P = 0.0205)

MVP

0.76

MPC

0.70

ClinPred

0.64

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.23

gMVP

0.56

Mutation Taster

=81/19

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.

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

Computational scores

Splicing

Publications

Other links and lift over