12-57012423-C-A

Variant names:

• chr12-57012423-C-A
• rs745977534
• NM_013251.4:c.322G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013251.4(TAC3):​c.322G>T​(p.Val108Phe) 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 benign outcome for this variant. 13/21 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: not found (cov: 32)
• Consequence: TAC3 NM_013251.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.804

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07153347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAC3	NM_013251.4	c.322G>T	p.Val108Phe	missense_variant	Exon 6 of 7	ENST00000458521.7	NP_037383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAC3	ENST00000458521.7	c.322G>T	p.Val108Phe	missense_variant	Exon 6 of 7	1	NM_013251.4	ENSP00000404056.2
TAC3	ENST00000300108.7	n.322G>T		non_coding_transcript_exon_variant	Exon 6 of 9	2		ENSP00000300108.3
TAC3	ENST00000379411.6	n.268G>T		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000368721.2
TAC3	ENST00000393867.5	n.*31G>T		non_coding_transcript_exon_variant	Exon 7 of 10	2		ENSP00000377445.1
TAC3	ENST00000393867.5	n.*31G>T		3_prime_UTR_variant	Exon 7 of 10	2		ENSP00000377445.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.023
DANN	Benign	0.38
DEOGEN2	Benign	0.11	T;.;T;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.55	.;.;T;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.41	N;.;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.29	N;D;.;N
REVEL	Uncertain	0.31
Sift	Benign	0.045	D;D;.;D
Sift4G	Benign	0.072	T;D;T;T
Polyphen		0.0020	B;B;B;B
Vest4		0.24
MutPred		0.16		Gain of catalytic residue at V108 (P = 0.0687);.;Gain of catalytic residue at V108 (P = 0.0687);Gain of catalytic residue at V108 (P = 0.0687);
MVP		0.17
MPC		0.72
ClinPred		0.092	T
GERP RS		-10
Varity_R		0.043
gMVP		0.21

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: rs745977534; hg19: chr12-57406207;