rs73334764

Variant names:

• chr12-57012450-A-G
• rs73334764
• NM_013251.4:c.295T>C

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.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. 16/21 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
• Publications: 5 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 (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 VariationId 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.

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.295T>C	p.Ser99Pro	missense splice_region	Exon 6 of 7	NP_037383.1	Q9UHF0-1
	TAC3	NM_001178054.2		c.241T>C	p.Ser81Pro	missense splice_region	Exon 5 of 6	NP_001171525.1	Q9UHF0-3
	TAC3	NR_033654.2		n.560T>C		splice_region non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAC3	ENST00000458521.7	TSL:1 MANE Select	c.295T>C	p.Ser99Pro	missense splice_region	Exon 6 of 7	ENSP00000404056.2	Q9UHF0-1
	TAC3	ENST00000441881.5	TSL:1	c.241T>C	p.Ser81Pro	missense splice_region	Exon 5 of 6	ENSP00000408208.1	Q9UHF0-3
	TAC3	ENST00000300108.7	TSL:2	n.295T>C		splice_region non_coding_transcript_exon	Exon 6 of 9	ENSP00000300108.3	Q9UHF0-1

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

GnomAD2 exomes AF: 0.00618 AC: 1553 AN: 251446 AF XY: 0.00455

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 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

African (AFR) AF: 0.0877 AC: 2934 AN: 33456

American (AMR) AF: 0.00494 AC: 221 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00537 AC: 31 AN: 5768

European-Non Finnish (NFE) AF: 0.000126 AC: 140 AN: 1111938

Other (OTH) AF: 0.00624 AC: 377 AN: 60380

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

African (AFR) AF: 0.0846 AC: 3503 AN: 41428

American (AMR) AF: 0.0101 AC: 154 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67978

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.00891 Hom.: 108

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.098
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.13	T
Sift4G	Benign	0.21	T
Polyphen		0.0	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
Mutation Taster		=82/18	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73334764; hg19: chr12-57406234;