chr12-57013379-T-A

Position:

• chr12-57013379-T-A

Variant summary

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

The NM_013251.4(TAC3):​c.218A>T​(p.Glu73Val) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E73G) has been classified 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: 0.152

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=0.25143403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAC3	NM_013251.4	c.218A>T	p.Glu73Val	missense_variant	4/7	ENST00000458521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAC3	ENST00000458521.7	c.218A>T	p.Glu73Val	missense_variant	4/7	1	NM_013251.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Dec 13, 2023

The c.218A>T (p.E73V) alteration is located in exon 4 (coding exon 3) of the TAC3 gene. This alteration results from a A to T substitution at nucleotide position 218, causing the glutamic acid (E) at amino acid position 73 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.30	N
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.6	M;M;M;M
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	D;D;.;D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.93	P;D;P;P
Vest4		0.27
MutPred		0.11		Loss of glycosylation at P71 (P = 0.0693);Loss of glycosylation at P71 (P = 0.0693);Loss of glycosylation at P71 (P = 0.0693);Loss of glycosylation at P71 (P = 0.0693);
MVP		0.85
MPC		1.6
ClinPred		0.97	D
GERP RS		2.2
Varity_R		0.21
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs367902220; hg19: chr12-57407163;