12-57013646-A-G

Variant names:

• chr12-57013646-A-G
• NM_013251.4:c.140T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_013251.4(TAC3):​c.140T>C​(p.Leu47Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TAC3 NM_013251.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

Genes affected

TAC3 (HGNC:11521): (tachykinin precursor 3) This gene encodes a member of the tachykinin family of secreted neuropeptides. The encoded preproprotein is proteolytically processed to generate the mature peptide, which is primarily expressed in the central and peripheral nervous systems and functions as a neurotransmitter. This peptide is the ligand for the neurokinin-3 receptor. This protein is also expressed in the outer syncytiotrophoblast of the placenta and may be associated with pregnancy-induced hypertension and pre-eclampsia. Mutations in this gene are associated with normosmic hypogonadotropic hypogonadism. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAC3	NM_013251.4	c.140T>C	p.Leu47Pro	missense_variant	Exon 3 of 7	ENST00000458521.7	NP_037383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAC3	ENST00000458521.7	c.140T>C	p.Leu47Pro	missense_variant	Exon 3 of 7	1	NM_013251.4	ENSP00000404056.2
TAC3	ENST00000300108.7	n.140T>C		non_coding_transcript_exon_variant	Exon 3 of 9	2		ENSP00000300108.3
TAC3	ENST00000379411.6	n.140T>C		non_coding_transcript_exon_variant	Exon 3 of 8	2		ENSP00000368721.2
TAC3	ENST00000393867.5	n.140T>C		non_coding_transcript_exon_variant	Exon 3 of 10	2		ENSP00000377445.1

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

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140T>C (p.L47P) alteration is located in exon 3 (coding exon 2) of the TAC3 gene. This alteration results from a T to C substitution at nucleotide position 140, causing the leucine (L) at amino acid position 47 to be replaced by a proline (P). 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	0.45
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.42	.;.;T;.
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.4	L;L;L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.74	N;N;.;N
REVEL	Uncertain	0.60
Sift	Benign	0.14	T;T;.;T
Sift4G	Benign	0.10	T;D;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.47
MutPred		0.85		Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);
MVP		0.84
MPC		0.85
ClinPred		0.91	D
GERP RS		6.0
Varity_R		0.26
gMVP		0.97

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: chr12-57407430;