NM_001127198.5:c.*244G>A

Variant names:

• chr17-78112904-C-T
• rs58948849
• NM_001127198.5:c.*244G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001127198.5(TMC6):​c.*244G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 562,554 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (19 hom.)
• Consequence: TMC6 NM_001127198.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0680
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (2148/152320) while in subpopulation AFR AF = 0.0484 (2012/41554). AF 95% confidence interval is 0.0467. There are 50 homozygotes in GnomAd4. There are 1001 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.*244G>A		3_prime_UTR_variant	Exon 20 of 20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.*244G>A		3_prime_UTR_variant	Exon 20 of 20	2	NM_001127198.5	ENSP00000465261.1

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2137 AN: 152202 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0119

GnomAD4 exome AF: 0.00187 AC: 769 AN: 410234 Hom.: 19 Cov.: 4 AF XY: 0.00161 AC XY: 347 AN XY: 215808

African (AFR) AF: 0.0490 AC: 520 AN: 10622

American (AMR) AF: 0.00536 AC: 78 AN: 14564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12726

East Asian (EAS) AF: 0.00 AC: 0 AN: 27606

South Asian (SAS) AF: 0.000145 AC: 6 AN: 41298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27900

Middle Eastern (MID) AF: 0.00486 AC: 9 AN: 1850

European-Non Finnish (NFE) AF: 0.000168 AC: 42 AN: 249738

Other (OTH) AF: 0.00476 AC: 114 AN: 23930

GnomAD4 genome AF: 0.0141 AC: 2148 AN: 152320 Hom.: 50 Cov.: 33 AF XY: 0.0134 AC XY: 1001 AN XY: 74488

African (AFR) AF: 0.0484 AC: 2012 AN: 41554

American (AMR) AF: 0.00627 AC: 96 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68028

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0123 Hom.: 2

Bravo AF: 0.0165

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.84
DANN	Benign	0.91
PhyloP100		-0.068
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs58948849; hg19: chr17-76108985;