12-57012393-G-A

Position:

chr12-57012393-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013251.4(TAC3):c.352C>T(p.Pro118Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

TAC3
NM_013251.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0160

Variant links:

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]

TAC3 links:

TAC3 (HGNC:):

TAC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06365371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAC3	NM_013251.4 linkuse as main transcript	c.352C>T	p.Pro118Ser	missense_variant	6/7	ENST00000458521.7	NP_037383.1	Q9UHF0-1A0A024RB47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TAC3	ENST00000458521.7 linkuse as main transcript	c.352C>T	p.Pro118Ser	missense_variant	6/7	1	NM_013251.4	ENSP00000404056.2	Q9UHF0-1
TAC3	ENST00000300108.7 linkuse as main transcript	n.352C>T		non_coding_transcript_exon_variant	6/9	2		ENSP00000300108.3	Q9UHF0-1
TAC3	ENST00000379411.6 linkuse as main transcript	n.298C>T		non_coding_transcript_exon_variant	5/8	2		ENSP00000368721.2	Q9UHF0-3
TAC3	ENST00000393867.5 linkuse as main transcript	n.*61C>T		non_coding_transcript_exon_variant	7/10	2		ENSP00000377445.1	Q9UHF0-2
TAC3	ENST00000393867.5 linkuse as main transcript	n.*61C>T		3_prime_UTR_variant	7/10	2		ENSP00000377445.1	Q9UHF0-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251432

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2024

The c.352C>T (p.P118S) alteration is located in exon 6 (coding exon 5) of the TAC3 gene. This alteration results from a C to T substitution at nucleotide position 352, causing the proline (P) at amino acid position 118 to be replaced by a serine (S). 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

0.069

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

2.2

DANN

Benign

0.35

DEOGEN2

Benign

0.28

T;.;T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.47

.;.;T;.

M_CAP

Benign

0.028

MetaRNN

Benign

0.064

T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.3

M;.;M;M

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

N;D;.;N

REVEL

Benign

0.088

Sift

Benign

0.23

T;T;.;T

Sift4G

Benign

0.098

T;T;T;T

Polyphen

0.0020

B;B;B;B

Vest4

0.079

MutPred

0.23

Loss of catalytic residue at P117 (P = 0.0094);.;Loss of catalytic residue at P117 (P = 0.0094);Loss of catalytic residue at P117 (P = 0.0094);

MVP

0.54

MPC

0.54

ClinPred

0.063

GERP RS

-1.6

Varity_R

0.020

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over