rs398122393

Variant names:

• chr12-57015736-GC-G
• rs398122393
• NM_013251.4:c.61delG

Your query was ambiguous. Multiple possible variants found:

• chr12-57015736-GC-G
• chr12-57015736-GC-GCC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_013251.4(TAC3):​c.61delG​(p.Ala21LeufsTer44) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TAC3 NM_013251.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.21
• Publications: 2 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: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-57015736-GC-G is Pathogenic according to our data. Variant chr12-57015736-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 66083.Status of the report is no_assertion_criteria_provided, 0 stars.

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.61delG	p.Ala21LeufsTer44	frameshift	Exon 2 of 7	NP_037383.1	Q9UHF0-1
	TAC3	NM_001178054.2		c.61delG	p.Ala21LeufsTer44	frameshift	Exon 2 of 6	NP_001171525.1	Q9UHF0-3
	TAC3	NR_033654.2		n.209delG		non_coding_transcript_exon	Exon 2 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAC3	ENST00000458521.7	TSL:1 MANE Select	c.61delG	p.Ala21LeufsTer44	frameshift	Exon 2 of 7	ENSP00000404056.2	Q9UHF0-1
	TAC3	ENST00000441881.5	TSL:1	c.61delG	p.Ala21LeufsTer44	frameshift	Exon 2 of 6	ENSP00000408208.1	Q9UHF0-3
	TAC3	ENST00000300108.7	TSL:2	n.61delG		non_coding_transcript_exon	Exon 2 of 9	ENSP00000300108.3	Q9UHF0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypogonadotropic hypogonadism 10 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=11/189	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398122393;

hg19: chr12-57409520;