12-57016407-G-A

Variant names:

• chr12-57016407-G-A
• rs2291855
• NM_013251.4:c.-26C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013251.4(TAC3):​c.-26C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0903 in 451,378 control chromosomes in the GnomAD database, including 2,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.090 (664 hom., cov: 31)
  • Exomes 𝑓: 0.090 (1369 hom.)
• Consequence: TAC3 NM_013251.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.258
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-57016407-G-A is Benign according to our data. Variant chr12-57016407-G-A is described in CliVar as Benign. Clinvar id is 1269499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-57016407-G-A is described in CliVar as Benign. Clinvar id is 1269499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-57016407-G-A is described in CliVar as Benign. Clinvar id is 1269499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-57016407-G-A is described in CliVar as Benign. Clinvar id is 1269499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-57016407-G-A is described in CliVar as Benign. Clinvar id is 1269499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-57016407-G-A is described in CliVar as Benign. Clinvar id is 1269499.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-57016407-G-A is described in CliVar as Benign. Clinvar id is 1269499.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAC3	NM_013251.4	c.-26C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	ENST00000458521.7	NP_037383.1
TAC3	NM_013251.4	c.-26C>T		5_prime_UTR_variant	Exon 1 of 7	ENST00000458521.7	NP_037383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAC3	ENST00000458521.7	c.-26C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1	NM_013251.4	ENSP00000404056.2
TAC3	ENST00000300108.7	n.-26C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9	2		ENSP00000300108.3
TAC3	ENST00000379411.6	n.-26C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	2		ENSP00000368721.2
TAC3	ENST00000393867.5	n.-26C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	2		ENSP00000377445.1
TAC3	ENST00000300108.7	n.-26C>T		non_coding_transcript_exon_variant	Exon 1 of 9	2		ENSP00000300108.3
TAC3	ENST00000379411.6	n.-26C>T		non_coding_transcript_exon_variant	Exon 1 of 8	2		ENSP00000368721.2
TAC3	ENST00000393867.5	n.-26C>T		non_coding_transcript_exon_variant	Exon 1 of 10	2		ENSP00000377445.1
TAC3	ENST00000458521.7	c.-26C>T		5_prime_UTR_variant	Exon 1 of 7	1	NM_013251.4	ENSP00000404056.2
TAC3	ENST00000300108.7	n.-26C>T		5_prime_UTR_variant	Exon 1 of 9	2		ENSP00000300108.3
TAC3	ENST00000379411.6	n.-26C>T		5_prime_UTR_variant	Exon 1 of 8	2		ENSP00000368721.2
TAC3	ENST00000393867.5	n.-26C>T		5_prime_UTR_variant	Exon 1 of 10	2		ENSP00000377445.1

Frequencies

GnomAD3 genomes AF: 0.0901 AC: 13700 AN: 152018 Hom.: 663 Cov.: 31

Gnomad AFR AF: 0.0813

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.0817

GnomAD2 exomes AF: 0.0958 AC: 12912 AN: 134772 AF XY: 0.0954

Gnomad AFR exome AF: 0.0803

Gnomad AMR exome AF: 0.0921

Gnomad ASJ exome AF: 0.0762

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0826

Gnomad OTH exome AF: 0.0917

GnomAD4 exome AF: 0.0904 AC: 27052 AN: 299242 Hom.: 1369 Cov.: 0 AF XY: 0.0902 AC XY: 15358 AN XY: 170224

African (AFR) AF: 0.0811 AC: 689 AN: 8492

American (AMR) AF: 0.0929 AC: 2526 AN: 27194

Ashkenazi Jewish (ASJ) AF: 0.0727 AC: 774 AN: 10648

East Asian (EAS) AF: 0.178 AC: 1628 AN: 9126

South Asian (SAS) AF: 0.101 AC: 5983 AN: 59486

European-Finnish (FIN) AF: 0.0985 AC: 1255 AN: 12736

Middle Eastern (MID) AF: 0.0951 AC: 108 AN: 1136

European-Non Finnish (NFE) AF: 0.0824 AC: 12890 AN: 156518

Other (OTH) AF: 0.0862 AC: 1199 AN: 13906

GnomAD4 genome AF: 0.0901 AC: 13710 AN: 152136 Hom.: 664 Cov.: 31 AF XY: 0.0929 AC XY: 6910 AN XY: 74384

African (AFR) AF: 0.0812 AC: 3371 AN: 41502

American (AMR) AF: 0.119 AC: 1816 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3472

East Asian (EAS) AF: 0.181 AC: 935 AN: 5162

South Asian (SAS) AF: 0.105 AC: 507 AN: 4824

European-Finnish (FIN) AF: 0.105 AC: 1115 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0804 AC: 5468 AN: 67994

Other (OTH) AF: 0.0851 AC: 179 AN: 2104

Alfa AF: 0.0810 Hom.: 237

Bravo AF: 0.0894

Asia WGS AF: 0.140 AC: 483 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.5
DANN	Benign	0.74
PhyloP100		-0.26
PromoterAI		-0.032	Neutral
Mutation Taster		=300/0	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: rs2291855; hg19: chr12-57410191;