Genetic Variant NM_001127198.5:c.2355G>T (chr17-78113211-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001127198.5(TMC6):c.2355G>T(p.Arg785Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,401,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R785T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TMC6
NM_001127198.5 missense, splice_region

Scores

Splicing: ADA: 0.9957

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.254

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

TMC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5 link	c.2355G>T	p.Arg785Ser	missense_variant, splice_region_variant	Exon 20 of 20	ENST00000590602.6	NP_001120670.1	Q7Z403-1A0A024R8V2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6 link	c.2355G>T	p.Arg785Ser	missense_variant, splice_region_variant	Exon 20 of 20	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1401706

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691528

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32236

American (AMR)

AF:

0.00

AC:

AN:

35860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25012

East Asian (EAS)

AF:

0.00

AC:

AN:

36850

South Asian (SAS)

AF:

0.00

AC:

AN:

79422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079746

Other (OTH)

AF:

0.00

AC:

AN:

58034

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

T;T;T;.;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.78

.;.;T;T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.083

T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.3

L;L;L;.;.

PhyloP100

0.25

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.62

.;N;N;N;.

REVEL

Benign

0.28

Sift

Benign

0.39

.;T;T;D;.

Sift4G

Benign

0.062

T;T;T;D;T

Polyphen

0.010

B;B;B;D;P

Vest4

0.29

MutPred

0.22

Gain of phosphorylation at R785 (P = 0.0073);Gain of phosphorylation at R785 (P = 0.0073);Gain of phosphorylation at R785 (P = 0.0073);.;.;

MVP

0.46

MPC

0.22

ClinPred

0.33

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.21

gMVP

0.45

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.10

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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NM_001127198.5:c.2355G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over