12-57012420-G-T

Variant names:

• chr12-57012420-G-T
• NM_013251.4:c.325C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013251.4(TAC3):​c.325C>A​(p.Pro109Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TAC3 NM_013251.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40485954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAC3	NM_013251.4	c.325C>A	p.Pro109Thr	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.325C>A	p.Pro109Thr	missense_variant	Exon 6 of 7	1	NM_013251.4	ENSP00000404056.2
TAC3	ENST00000300108.7	n.325C>A		non_coding_transcript_exon_variant	Exon 6 of 9	2		ENSP00000300108.3
TAC3	ENST00000379411.6	n.271C>A		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000368721.2
TAC3	ENST00000393867.5	n.*34C>A		non_coding_transcript_exon_variant	Exon 7 of 10	2		ENSP00000377445.1
TAC3	ENST00000393867.5	n.*34C>A		3_prime_UTR_variant	Exon 7 of 10	2		ENSP00000377445.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;T;T
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.74	.;.;T;.
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Uncertain	2.1	M;.;M;M
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.6	D;D;.;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.93	P;D;P;P
Vest4		0.33
MutPred		0.34		Loss of disorder (P = 0.0501);.;Loss of disorder (P = 0.0501);Loss of disorder (P = 0.0501);
MVP		0.79
MPC		1.5
ClinPred		0.89	D
GERP RS		3.3
Varity_R		0.15
gMVP		0.48

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: chr12-57406204;