12-57012660-T-C

Variant names:

• chr12-57012660-T-C
• rs733629
• NM_013251.4:c.292+162A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013251.4(TAC3):​c.292+162A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0858 in 1,612,812 control chromosomes in the GnomAD database, including 6,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (662 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5595 hom.)
• Consequence: TAC3 NM_013251.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.27
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 10 with or without anosmia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-57012660-T-C is Benign according to our data. Variant chr12-57012660-T-C is described in ClinVar as Benign. ClinVar VariationId is 675709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013251.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAC3	NM_013251.4	MANE Select	c.292+162A>G		intron	N/A	NP_037383.1	Q9UHF0-1
	TAC3	NM_001178054.2		c.239-208A>G		intron	N/A	NP_001171525.1	Q9UHF0-3
	TAC3	NR_033654.2		n.518A>G		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAC3	ENST00000458521.7	TSL:1 MANE Select	c.292+162A>G		intron	N/A	ENSP00000404056.2	Q9UHF0-1
	TAC3	ENST00000441881.5	TSL:1	c.239-208A>G		intron	N/A	ENSP00000408208.1	Q9UHF0-3
	TAC3	ENST00000357616.7	TSL:1	n.370A>G		non_coding_transcript_exon	Exon 6 of 8	ENSP00000350236.3	Q9UHF0-2

Frequencies

GnomAD3 genomes AF: 0.0906 AC: 13771 AN: 152004 Hom.: 663 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0736

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0811

Gnomad OTH AF: 0.0818

GnomAD2 exomes AF: 0.0956 AC: 23992 AN: 250930 AF XY: 0.0955

Gnomad AFR exome AF: 0.0831

Gnomad AMR exome AF: 0.0883

Gnomad ASJ exome AF: 0.0762

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0840

Gnomad OTH exome AF: 0.0888

GnomAD4 exome AF: 0.0853 AC: 124527 AN: 1460690 Hom.: 5595 Cov.: 32 AF XY: 0.0852 AC XY: 61921 AN XY: 726680

African (AFR) AF: 0.0833 AC: 2788 AN: 33476

American (AMR) AF: 0.0906 AC: 4049 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0742 AC: 1939 AN: 26130

East Asian (EAS) AF: 0.140 AC: 5537 AN: 39686

South Asian (SAS) AF: 0.102 AC: 8726 AN: 85428

European-Finnish (FIN) AF: 0.103 AC: 5488 AN: 53374

Middle Eastern (MID) AF: 0.0890 AC: 513 AN: 5766

European-Non Finnish (NFE) AF: 0.0812 AC: 90309 AN: 1111742

Other (OTH) AF: 0.0858 AC: 5178 AN: 60374

GnomAD4 genome AF: 0.0906 AC: 13777 AN: 152122 Hom.: 662 Cov.: 32 AF XY: 0.0933 AC XY: 6938 AN XY: 74354

African (AFR) AF: 0.0816 AC: 3388 AN: 41510

American (AMR) AF: 0.119 AC: 1815 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0736 AC: 255 AN: 3464

East Asian (EAS) AF: 0.182 AC: 943 AN: 5168

South Asian (SAS) AF: 0.106 AC: 511 AN: 4820

European-Finnish (FIN) AF: 0.105 AC: 1111 AN: 10574

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0811 AC: 5512 AN: 67992

Other (OTH) AF: 0.0833 AC: 176 AN: 2112

Alfa AF: 0.0833 Hom.: 1209

Bravo AF: 0.0900

Asia WGS AF: 0.135 AC: 468 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Uncertain	0.99
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs733629; hg19: chr12-57406444; COSMIC: COSV55648549; COSMIC: COSV55648549;