chr11-117206025-G-A

Position:

• chr11-117206025-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004716.4(PCSK7):​c.2330C>T​(p.Pro777Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.027 in 1,222,646 control chromosomes in the GnomAD database, including 621 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (67 hom., cov: 30)
  • Exomes 𝑓: 0.028 (554 hom.)
• Consequence: PCSK7 NM_004716.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.729

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016633868).
• BP6: Variant 11-117206025-G-A is Benign according to our data. Variant chr11-117206025-G-A is described in ClinVar as [Benign]. Clinvar id is 790849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK7	NM_004716.4	c.2330C>T	p.Pro777Leu	missense_variant	17/17	ENST00000320934.8	NP_004707.2
TAGLN	NM_003186.5	c.*1666G>A		3_prime_UTR_variant	5/5	ENST00000392951.9	NP_003177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK7	ENST00000320934.8	c.2330C>T	p.Pro777Leu	missense_variant	17/17	1	NM_004716.4	ENSP00000325917	P1
TAGLN	ENST00000392951.9	c.*1666G>A		3_prime_UTR_variant	5/5	1	NM_003186.5	ENSP00000376678	P1
	ENST00000624094.1	n.1059G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3542 AN: 150762 Hom.: 67 Cov.: 30

Gnomad AFR AF: 0.00597

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.0382

Gnomad SAS AF: 0.0915

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0316

Gnomad OTH AF: 0.0194

GnomAD3 exomes AF: 0.0292 AC: 3908 AN: 133882 Hom.: 99 AF XY: 0.0319 AC XY: 2232 AN XY: 70032

Gnomad AFR exome AF: 0.00501

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.0362

Gnomad SAS exome AF: 0.0826

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.0264

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0276 AC: 29528 AN: 1071766 Hom.: 554 Cov.: 15 AF XY: 0.0293 AC XY: 15629 AN XY: 533502

Gnomad4 AFR exome AF: 0.00408

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0352

Gnomad4 SAS exome AF: 0.0797

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0269

GnomAD4 genome AF: 0.0235 AC: 3543 AN: 150880 Hom.: 67 Cov.: 30 AF XY: 0.0247 AC XY: 1821 AN XY: 73704

Gnomad4 AFR AF: 0.00595

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.0383

Gnomad4 SAS AF: 0.0920

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0316

Gnomad4 OTH AF: 0.0187

Alfa AF: 0.0252 Hom.: 10

Bravo AF: 0.0210

ESP6500AA AF: 0.00380 AC: 16

ESP6500EA AF: 0.0223 AC: 185

ExAC AF: 0.0205 AC: 2387

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.1
DANN	Benign	0.52
DEOGEN2	Benign	0.0095	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.63	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.50
ClinPred		0.00097	T
GERP RS		1.8
Varity_R		0.017
gMVP		0.11

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: rs201598301; hg19: chr11-117076741; COSMIC: COSV54064238; COSMIC: COSV54064238;