rs508487

Positions:

• chr11-117204850-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004716.4(PCSK7):​c.*1147G>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 0.0625 in 267,740 control chromosomes in the GnomAD database, including 718 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 0.055 (321 hom., cov: 32)
  • Exomes 𝑓: 0.073 (397 hom.)
• Consequence: PCSK7 NM_004716.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284

Genes affected

PCSK7 (HGNC:8748): (proprotein convertase subtilisin/kexin type 7) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. It encodes a type 1 membrane bound protease that is expressed in many tissues, including neuroendocrine, liver, gut, and brain. The encoded protein undergoes an initial autocatalytic processing event in the ER and then sorts to the trans-Golgi network through endosomes where a second autocatalytic event takes place and the catalytic activity is acquired. This gene encodes one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. It can process proalbumin and is thought to be responsible for the activation of HIV envelope glycoproteins gp160 and gp140. This gene has been implicated in the transcriptional regulation of housekeeping genes and plays a role in the regulation of iron metabolism. A t(11;14)(q23;q32) chromosome translocation associated with B-cell lymphoma occurs between this gene and its inverted counterpart. [provided by RefSeq, Feb 2014]

TAGLN (HGNC:11553): (transgelin) This gene encodes a shape change and transformation sensitive actin-binding protein which belongs to the calponin family. It is ubiquitously expressed in vascular and visceral smooth muscle, and is an early marker of smooth muscle differentiation. The encoded protein is thought to be involved in calcium-independent smooth muscle contraction. It acts as a tumor suppressor, and the loss of its expression is an early event in cell transformation and the development of some tumors, coinciding with cellular plasticity. The encoded protein has a domain architecture consisting of an N-terminal calponin homology (CH) domain and a C-terminal calponin-like (CLIK) domain. Mice with a knockout of the orthologous gene are viable and fertile but their vascular smooth muscle cells exhibit alterations in the distribution of the actin filament and changes in cytoskeletal organization. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK7	NM_004716.4	c.*1147G>A		3_prime_UTR_variant	17/17	ENST00000320934.8	NP_004707.2
TAGLN	NM_003186.5	c.*491C>T		3_prime_UTR_variant	5/5	ENST00000392951.9	NP_003177.2
TAGLN	NM_001001522.2	c.*491C>T		3_prime_UTR_variant	5/5		NP_001001522.1
PCSK7	XM_006718940.5	c.*1147G>A		3_prime_UTR_variant	10/10		XP_006719003.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK7	ENST00000320934	c.*1147G>A		3_prime_UTR_variant	17/17	1	NM_004716.4	ENSP00000325917.3
TAGLN	ENST00000392951.9	c.*491C>T		3_prime_UTR_variant	5/5	1	NM_003186.5	ENSP00000376678.4

Frequencies

GnomAD3 genomes AF: 0.0547 AC: 8305 AN: 151830 Hom.: 318 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0882

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0594

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0579

GnomAD4 exome AF: 0.0728 AC: 8432 AN: 115814 Hom.: 397 Cov.: 0 AF XY: 0.0762 AC XY: 4508 AN XY: 59154

Gnomad4 AFR exome AF: 0.00910

Gnomad4 AMR exome AF: 0.0588

Gnomad4 ASJ exome AF: 0.0890

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.0705

Gnomad4 NFE exome AF: 0.0608

Gnomad4 OTH exome AF: 0.0647

GnomAD4 genome AF: 0.0547 AC: 8311 AN: 151926 Hom.: 321 Cov.: 32 AF XY: 0.0566 AC XY: 4200 AN XY: 74220

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.0703

Gnomad4 ASJ AF: 0.0882

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.0594

Gnomad4 NFE AF: 0.0631

Gnomad4 OTH AF: 0.0636

Alfa AF: 0.0616 Hom.: 533

Bravo AF: 0.0510

Asia WGS AF: 0.116 AC: 401 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs508487; hg19: chr11-117075566;