3-111999547-T-G

Position:

• chr3-111999547-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000478951.6(TAGLN3):​c.125T>G​(p.Ile42Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TAGLN3 ENST00000478951.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAGLN3	NM_001008272.2	c.125T>G	p.Ile42Arg	missense_variant	2/5	ENST00000478951.6	NP_001008273.1
TAGLN3	NM_001008273.2	c.125T>G	p.Ile42Arg	missense_variant	1/4		NP_001008274.1
TAGLN3	NM_013259.3	c.125T>G	p.Ile42Arg	missense_variant	2/5		NP_037391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAGLN3	ENST00000478951.6	c.125T>G	p.Ile42Arg	missense_variant	2/5	1	NM_001008272.2	ENSP00000419105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461856 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

May 30, 2023

The c.125T>G (p.I42R) alteration is located in exon 2 (coding exon 1) of the TAGLN3 gene. This alteration results from a T to G substitution at nucleotide position 125, causing the isoleucine (I) at amino acid position 42 to be replaced by an arginine (R). 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	0.13
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;D;D;D;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	.;T;.;.;T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.6	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.26	B;B;B;B;.
Vest4		0.54
MutPred		0.65		Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);
MVP		0.20
MPC		1.9
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.75
gMVP		0.79

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: rs1199260399; hg19: chr3-111718394;