dbSNP rs146371375: TMC6:p.Ala280Thr (chr17-78124577-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001127198.5(TMC6):c.838G>A(p.Ala280Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000622 in 1,612,106 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0030 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.312

Publications

4 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036548376).

BP6

Variant 17-78124577-C-T is Benign according to our data. Variant chr17-78124577-C-T is described in ClinVar as Benign. ClinVar VariationId is 456017.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00305 (464/152286) while in subpopulation AFR AF = 0.0105 (438/41572). AF 95% confidence interval is 0.00972. There are 7 homozygotes in GnomAd4. There are 218 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 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	UniProt
TMC6	NM_001127198.5	MANE Select	c.838G>A	p.Ala280Thr	missense	Exon 8 of 20	NP_001120670.1	Q7Z403-1
TMC6	NM_001321185.1		c.838G>A	p.Ala280Thr	missense	Exon 8 of 20	NP_001308114.1	Q7Z403-1
TMC6	NM_001374596.1		c.838G>A	p.Ala280Thr	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.838G>A	p.Ala280Thr	missense	Exon 8 of 20	ENSP00000465261.1	Q7Z403-1
TMC6	ENST00000322914.7	TSL:1	c.838G>A	p.Ala280Thr	missense	Exon 8 of 20	ENSP00000313408.2	Q7Z403-1
TMC6	ENST00000392467.7	TSL:1	c.838G>A	p.Ala280Thr	missense	Exon 7 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.00304

AC:

463

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000805

AC:

195

AN:

242200

AF XY:

0.000639

show subpopulations

Gnomad AFR exome

AF:

0.00981

Gnomad AMR exome

AF:

0.000731

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000558

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.000369

AC:

538

AN:

1459820

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

245

AN XY:

726174

show subpopulations

African (AFR)

AF:

0.0104

AC:

348

AN:

33466

American (AMR)

AF:

0.000537

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00123

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51866

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000531

AC:

AN:

1111766

Other (OTH)

AF:

0.000829

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

108

144

180

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:

0.00305

AC:

464

AN:

152286

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

218

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0105

AC:

438

AN:

41572

American (AMR)

AF:

0.00105

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67992

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

119

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:

0.00103

Hom.:

Bravo

AF:

0.00340

ESP6500AA

AF:

0.00781

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.00101

AC:

122

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000297

ClinVar

ClinVar submissions

Significance:Benign

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

0.070

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

3.0

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0059

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.31

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.14

REVEL

Benign

0.038

Sift

Benign

0.65

Sift4G

Benign

0.65

Polyphen

0.0010

Vest4

0.11

MVP

0.27

MPC

0.15

ClinPred

0.00084

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.013

gMVP

0.28

Mutation Taster

=298/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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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