rs147856997

Positions:

• chr17-78122693-G-A
• chr17-78122693-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001127198.5(TMC6):​c.1139C>T​(p.Ala380Val) variant causes a missense change. The variant allele was found at a frequency of 0.000495 in 1,611,794 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.96

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009143323).
• BP6: Variant 17-78122693-G-A is Benign according to our data. Variant chr17-78122693-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 456002.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 = 0.00279 (425/152386) while in subpopulation AFR AF= 0.00959 (399/41594). AF 95% confidence interval is 0.00882. There are 1 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.1139C>T	p.Ala380Val	missense_variant	10/20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.1139C>T	p.Ala380Val	missense_variant	10/20	2	NM_001127198.5	ENSP00000465261.1

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 425 AN: 152268 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00962

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000597 AC: 147 AN: 246162 Hom.: 1 AF XY: 0.000524 AC XY: 70 AN XY: 133620

Gnomad AFR exome AF: 0.00844

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000256 AC: 373 AN: 1459408 Hom.: 0 Cov.: 31 AF XY: 0.000222 AC XY: 161 AN XY: 725872

Gnomad4 AFR exome AF: 0.00909

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.000680

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152386 Hom.: 1 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74524

Gnomad4 AFR AF: 0.00959

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000767 Hom.: 0

Bravo AF: 0.00334

ESP6500AA AF: 0.00863 AC: 38

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000709 AC: 86

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Epidermodysplasia verruciformis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;.;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0091	T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.8	M;M;M;M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	.;D;D;D;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	.;D;D;T;.;.
Sift4G	Benign	0.12	T;T;T;D;T;D
Polyphen		0.78	P;P;P;D;P;D
Vest4		0.80
MVP		0.41
MPC		0.65
ClinPred		0.041	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs147856997; hg19: chr17-76118774;