11-117203355-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003186.5(TAGLN):c.229G>C(p.Val77Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00147 in 1,614,176 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00085 (19 hom.)
• Consequence: TAGLN NM_003186.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.86

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010215431).
• BP6: Variant 11-117203355-G-C is Benign according to our data. Variant chr11-117203355-G-C is described in ClinVar as [Benign]. Clinvar id is 791178.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00743 (1132/152286) while in subpopulation AFR AF= 0.0259 (1078/41566). AF 95% confidence interval is 0.0246. There are 8 homozygotes in gnomad4. There are 526 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAGLN	NM_003186.5	c.229G>C	p.Val77Leu	missense_variant	3/5	ENST00000392951.9
TAGLN	NM_001001522.2	c.229G>C	p.Val77Leu	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAGLN	ENST00000392951.9	c.229G>C	p.Val77Leu	missense_variant	3/5	1	NM_003186.5	P1

Frequencies

GnomAD3 genomes AF: 0.00743 AC: 1130 AN: 152166 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00196 AC: 492 AN: 251488 Hom.: 9 AF XY: 0.00148 AC XY: 201 AN XY: 135918

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000852 AC: 1246 AN: 1461890 Hom.: 19 Cov.: 31 AF XY: 0.000744 AC XY: 541 AN XY: 727248

Gnomad4 AFR exome AF: 0.0290

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00743 AC: 1132 AN: 152286 Hom.: 8 Cov.: 33 AF XY: 0.00706 AC XY: 526 AN XY: 74456

Gnomad4 AFR AF: 0.0259

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00132 Hom.: 1

Bravo AF: 0.00825

ESP6500AA AF: 0.0239 AC: 105

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00245 AC: 297

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

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

Dec 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D;D;.;D;D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.1	M;M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.026	D;D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D;D
Polyphen		0.010	B;B;B;.;B;B
Vest4		0.45
MutPred		0.44		Loss of methylation at K78 (P = 0.0631);Loss of methylation at K78 (P = 0.0631);Loss of methylation at K78 (P = 0.0631);Loss of methylation at K78 (P = 0.0631);Loss of methylation at K78 (P = 0.0631);Loss of methylation at K78 (P = 0.0631);
MVP		0.97
MPC		0.21
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.38
gMVP		0.38

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: rs36112166; hg19: chr11-117074071;