Genetic Variant TAGLN3:p.Ala123Glu (chr3-112011775-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001008272.2(TAGLN3):c.368C>A(p.Ala123Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TAGLN3
NM_001008272.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.72

Variant links:

Genes affected

TAGLN3 (HGNC:29868): (transgelin 3) Predicted to be involved in central nervous system development. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be active in cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

TAGLN3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAGLN3	NM_001008272.2 link	c.368C>A	p.Ala123Glu	missense_variant	Exon 4 of 5	ENST00000478951.6	NP_001008273.1	Q9UI15
TAGLN3	NM_001008273.2 link	c.368C>A	p.Ala123Glu	missense_variant	Exon 3 of 4		NP_001008274.1	Q9UI15
TAGLN3	NM_013259.3 link	c.368C>A	p.Ala123Glu	missense_variant	Exon 4 of 5		NP_037391.2	Q9UI15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAGLN3	ENST00000478951.6 link	c.368C>A	p.Ala123Glu	missense_variant	Exon 4 of 5	1	NM_001008272.2	ENSP00000419105.1		Q9UI15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459650

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368C>A (p.A123E) alteration is located in exon 4 (coding exon 3) of the TAGLN3 gene. This alteration results from a C to A substitution at nucleotide position 368, causing the alanine (A) at amino acid position 123 to be replaced by a glutamic acid (E). 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

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;D;D;D;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;.;.;D

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.75

D;D;D;D;D

MetaSVM

Uncertain

0.0019

MutationAssessor

Uncertain

2.6

M;M;M;M;.

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.3

D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.011

D;D;D;D;T

Sift4G

Benign

0.081

T;T;T;T;T

Polyphen

0.95

P;P;P;P;.

Vest4

0.80

MutPred

0.49

Gain of disorder (P = 0.0876);Gain of disorder (P = 0.0876);Gain of disorder (P = 0.0876);Gain of disorder (P = 0.0876);.;

MVP

0.49

MPC

2.0

ClinPred

0.97

GERP RS

6.0

Varity_R

0.64

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over