rs75400929

Variant names:

• chr17-78121043-G-A
• rs75400929
• NM_001127198.5:c.1505C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-78121043-G-A
• chr17-78121043-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127198.5(TMC6):​c.1505C>T​(p.Pro502Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00827 in 1,613,348 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P502P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (105 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.46
• Publications: 8 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: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• epidermodysplasia verruciformis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065681934).
• BP6: Variant 17-78121043-G-A is Benign according to our data. Variant chr17-78121043-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 456008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00724 (1102/152300) while in subpopulation NFE AF = 0.00906 (616/68012). AF 95% confidence interval is 0.00847. There are 15 homozygotes in GnomAd4. There are 600 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	NM_001127198.5	MANE Select	c.1505C>T	p.Pro502Leu	missense	Exon 12 of 20	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.1505C>T	p.Pro502Leu	missense	Exon 12 of 20	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.1505C>T	p.Pro502Leu	missense	Exon 12 of 20	NP_001361525.1	Q7Z403-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	ENST00000590602.6	TSL:2 MANE Select	c.1505C>T	p.Pro502Leu	missense	Exon 12 of 20	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.1505C>T	p.Pro502Leu	missense	Exon 12 of 20	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.1505C>T	p.Pro502Leu	missense	Exon 11 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1102 AN: 152182 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00906

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00849 AC: 2126 AN: 250436 AF XY: 0.00807

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.00976

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00838 AC: 12247 AN: 1461048 Hom.: 105 Cov.: 32 AF XY: 0.00803 AC XY: 5838 AN XY: 726844

African (AFR) AF: 0.000657 AC: 22 AN: 33478

American (AMR) AF: 0.00141 AC: 63 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00217 AC: 187 AN: 86258

European-Finnish (FIN) AF: 0.0390 AC: 2050 AN: 52610

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00853 AC: 9489 AN: 1111996

Other (OTH) AF: 0.00672 AC: 406 AN: 60388

GnomAD4 genome AF: 0.00724 AC: 1102 AN: 152300 Hom.: 15 Cov.: 32 AF XY: 0.00806 AC XY: 600 AN XY: 74470

African (AFR) AF: 0.00125 AC: 52 AN: 41560

American (AMR) AF: 0.000719 AC: 11 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

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

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.0371 AC: 394 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00906 AC: 616 AN: 68012

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00774 Hom.: 36

Bravo AF: 0.00447

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00858 AC: 1042

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00640

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epidermodysplasia verruciformis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0066	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.69
MPC		0.68
ClinPred		0.053	T
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.79
gMVP		0.62
Mutation Taster		=73/27	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: rs75400929; hg19: chr17-76117124; COSMIC: COSV59809884; COSMIC: COSV59809884;