11-117204332-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_003186.5(TAGLN):c.579C>T(p.Tyr193=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,614,228 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (45 hom.)
• Consequence: TAGLN NM_003186.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.105

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-117204332-C-T is Benign according to our data. Variant chr11-117204332-C-T is described in ClinVar as [Benign]. Clinvar id is 787098.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.105 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0138 (2108/152338) while in subpopulation AFR AF= 0.0442 (1838/41562). AF 95% confidence interval is 0.0425. There are 42 homozygotes in gnomad4. There are 1016 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2101 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAGLN	NM_003186.5	c.579C>T	p.Tyr193=	synonymous_variant	5/5	ENST00000392951.9
TAGLN	NM_001001522.2	c.579C>T	p.Tyr193=	synonymous_variant	5/5
PCSK7	NM_004716.4			downstream_gene_variant		ENST00000320934.8
PCSK7	XM_006718940.5			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAGLN	ENST00000392951.9	c.579C>T	p.Tyr193=	synonymous_variant	5/5	1	NM_003186.5	P1
PCSK7	ENST00000320934.8			downstream_gene_variant		1	NM_004716.4	P1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2101 AN: 152220 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00440 AC: 1105 AN: 251396 Hom.: 16 AF XY: 0.00341 AC XY: 463 AN XY: 135864

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000624

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00201 AC: 2941 AN: 1461890 Hom.: 45 Cov.: 31 AF XY: 0.00188 AC XY: 1367 AN XY: 727246

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.00402

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000432

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.0138 AC: 2108 AN: 152338 Hom.: 42 Cov.: 32 AF XY: 0.0136 AC XY: 1016 AN XY: 74504

Gnomad4 AFR AF: 0.0442

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00784 Hom.: 13

Bravo AF: 0.0160

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 09, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	7.9
Dann	Benign	0.88

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: rs11547377; hg19: chr11-117075048;