12-57012450-A-G

Position:

• chr12-57012450-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013251.4(TAC3):​c.295T>C​(p.Ser99Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,613,774 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (174 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (142 hom.)
• Consequence: TAC3 NM_013251.4 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0980

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017648637).
• BP6: Variant 12-57012450-A-G is Benign according to our data. Variant chr12-57012450-A-G is described in ClinVar as [Benign]. Clinvar id is 139385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TAC3	NM_013251.4	c.295T>C	p.Ser99Pro	missense_variant, splice_region_variant	6/7	ENST00000458521.7	NP_037383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TAC3	ENST00000458521.7	c.295T>C	p.Ser99Pro	missense_variant, splice_region_variant	6/7	1	NM_013251.4	ENSP00000404056	P1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3702 AN: 151908 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00618 AC: 1553 AN: 251446 Hom.: 63 AF XY: 0.00455 AC XY: 619 AN XY: 135902

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00255 AC: 3725 AN: 1461748 Hom.: 142 Cov.: 32 AF XY: 0.00220 AC XY: 1602 AN XY: 727180

Gnomad4 AFR exome AF: 0.0877

Gnomad4 AMR exome AF: 0.00494

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000126

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.0245 AC: 3719 AN: 152026 Hom.: 174 Cov.: 32 AF XY: 0.0240 AC XY: 1785 AN XY: 74308

Gnomad4 AFR AF: 0.0846

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.00450 Hom.: 37

Bravo AF: 0.0279

ESP6500AA AF: 0.0788 AC: 347

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00749 AC: 910

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	2.3
DANN	Benign	0.88
DEOGEN2	Benign	0.088	T;.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.37	.;.;T;.
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.13	T;D;.;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.14
MVP		0.29
MPC		0.78
ClinPred		0.00053	T
GERP RS		-0.86
Varity_R		0.066
gMVP		0.13

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: rs73334764; hg19: chr12-57406234;