11-117203191-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003186.5(TAGLN):c.178G>A(p.Val60Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,589,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: TAGLN NM_003186.5 missense, splice_region
• Scores: Splicing: ADA: 0.9884
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAGLN	NM_003186.5	c.178G>A	p.Val60Met	missense_variant, splice_region_variant	2/5	ENST00000392951.9
TAGLN	NM_001001522.2	c.178G>A	p.Val60Met	missense_variant, splice_region_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAGLN	ENST00000392951.9	c.178G>A	p.Val60Met	missense_variant, splice_region_variant	2/5	1	NM_003186.5	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000764 AC: 18 AN: 235484 Hom.: 0 AF XY: 0.000103 AC XY: 13 AN XY: 126616

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000195 AC: 280 AN: 1436986 Hom.: 0 Cov.: 31 AF XY: 0.000214 AC XY: 152 AN XY: 711070

Gnomad4 AFR exome AF: 0.0000606

Gnomad4 AMR exome AF: 0.0000698

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000225

Gnomad4 OTH exome AF: 0.000439

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74484

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000232 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.178G>A (p.V60M) alteration is located in exon 2 (coding exon 1) of the TAGLN gene. This alteration results from a G to A substitution at nucleotide position 178, causing the valine (V) at amino acid position 60 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D;D;.;D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.50	N
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.2	M;M;M;.;M;M
MutationTaster	Benign	0.85	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.019	D;D;D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;T;D;D
Polyphen		0.89	P;P;P;.;P;P
Vest4		0.19
MVP		0.96
MPC		0.21
ClinPred		0.070	T
GERP RS		4.7
Varity_R		0.077
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.86
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: rs149213147; hg19: chr11-117073907; COSMIC: COSV54064334; COSMIC: COSV54064334;