chr11-117203847-G-T

Variant names:

• chr11-117203847-G-T
• NM_003186.5:c.424G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003186.5(TAGLN):​c.424G>T​(p.Asp142Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAGLN NM_003186.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.42

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3589571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAGLN	NM_003186.5	c.424G>T	p.Asp142Tyr	missense_variant	Exon 4 of 5	ENST00000392951.9	NP_003177.2
TAGLN	NM_001001522.2	c.424G>T	p.Asp142Tyr	missense_variant	Exon 4 of 5		NP_001001522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAGLN	ENST00000392951.9	c.424G>T	p.Asp142Tyr	missense_variant	Exon 4 of 5	1	NM_003186.5	ENSP00000376678.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.424G>T (p.D142Y) alteration is located in exon 4 (coding exon 3) of the TAGLN gene. This alteration results from a G to T substitution at nucleotide position 424, causing the aspartic acid (D) at amino acid position 142 to be replaced by a tyrosine (Y). 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	Pathogenic	0.70
BayesDel_addAF	Benign	0.0059	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;D;D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;.;.;.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.054	T;T;T;T;T
Polyphen		0.56	P;P;P;P;P
Vest4		0.49
MutPred		0.44		Loss of ubiquitination at K140 (P = 0.0446);Loss of ubiquitination at K140 (P = 0.0446);Loss of ubiquitination at K140 (P = 0.0446);Loss of ubiquitination at K140 (P = 0.0446);Loss of ubiquitination at K140 (P = 0.0446);
MVP		0.65
MPC		0.27
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-117074563;