3-112013467-C-G

Variant names:

• chr3-112013467-C-G
• rs759725437
• NM_001008272.2:c.516C>G

Variant summary

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

The NM_001008272.2(TAGLN3):​c.516C>G​(p.Asn172Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TAGLN3 NM_001008272.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0920

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 rank	MANE	Protein	UniProt
TAGLN3	NM_001008272.2	c.516C>G	p.Asn172Lys	missense_variant	Exon 5 of 5	ENST00000478951.6	NP_001008273.1
TAGLN3	NM_001008273.2	c.516C>G	p.Asn172Lys	missense_variant	Exon 4 of 4		NP_001008274.1
TAGLN3	NM_013259.3	c.516C>G	p.Asn172Lys	missense_variant	Exon 5 of 5		NP_037391.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAGLN3	ENST00000478951.6	c.516C>G	p.Asn172Lys	missense_variant	Exon 5 of 5	1	NM_001008272.2	ENSP00000419105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251128 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135722

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.516C>G (p.N172K) alteration is located in exon 5 (coding exon 4) of the TAGLN3 gene. This alteration results from a C to G substitution at nucleotide position 516, causing the asparagine (N) at amino acid position 172 to be replaced by a lysine (K). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	.;D;.;.;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L;L;L;L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.12
Sift	Benign	0.16	T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T
Polyphen		0.075	B;B;B;B;.
Vest4		0.57
MutPred		0.36		Gain of ubiquitination at N172 (P = 0.0069);Gain of ubiquitination at N172 (P = 0.0069);Gain of ubiquitination at N172 (P = 0.0069);Gain of ubiquitination at N172 (P = 0.0069);.;
MVP		0.20
MPC		1.5
ClinPred		0.79	D
GERP RS		-0.66
Varity_R		0.22
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759725437; hg19: chr3-111732314;