Genetic Variant TAC3:c.*19C>T (chr12-57010271-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013251.4(TAC3):c.*19C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 448,830 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 41 hom., cov: 32)

Exomes 𝑓: 0.020 ( 98 hom. )

Consequence

TAC3
NM_013251.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.860

Publications

0 publications found

Variant links:

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

TAC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 12-57010271-G-A is Benign according to our data. Variant chr12-57010271-G-A is described in ClinVar as Benign. ClinVar VariationId is 1294258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0183 (2782/152114) while in subpopulation NFE AF = 0.0266 (1810/67992). AF 95% confidence interval is 0.0256. There are 41 homozygotes in GnomAd4. There are 1433 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TAC3	NM_013251.4	MANE Select	c.*19C>T	3_prime_UTR	Exon 7 of 7	NP_037383.1	Q9UHF0-1
TAC3	NM_001178054.2		c.*19C>T	3_prime_UTR	Exon 6 of 6	NP_001171525.1	Q9UHF0-3
TAC3	NR_033654.2		n.650C>T	non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TAC3	ENST00000458521.7	TSL:1 MANE Select	c.*19C>T	3_prime_UTR	Exon 7 of 7	ENSP00000404056.2	Q9UHF0-1
TAC3	ENST00000441881.5	TSL:1	c.*19C>T	3_prime_UTR	Exon 6 of 6	ENSP00000408208.1	Q9UHF0-3
TAC3	ENST00000300108.7	TSL:2	n.*354C>T	non_coding_transcript_exon	Exon 9 of 9	ENSP00000300108.3	Q9UHF0-1

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2783

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00727

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00520

Gnomad FIN

AF:

0.0568

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0266

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0161

AC:

2049

AN:

127128

AF XY:

0.0161

show subpopulations

Gnomad AFR exome

AF:

0.00498

Gnomad AMR exome

AF:

0.00544

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0652

Gnomad NFE exome

AF:

0.0253

Gnomad OTH exome

AF:

0.0169

GnomAD4 exome

AF:

0.0205

AC:

6080

AN:

296716

Hom.:

Cov.:

AF XY:

0.0191

AC XY:

3229

AN XY:

168864

show subpopulations

African (AFR)

AF:

0.00404

AC:

AN:

8412

American (AMR)

AF:

0.00546

AC:

147

AN:

26922

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

142

AN:

10626

East Asian (EAS)

AF:

0.00

AC:

AN:

9124

South Asian (SAS)

AF:

0.00701

AC:

413

AN:

58900

European-Finnish (FIN)

AF:

0.0693

AC:

850

AN:

12262

Middle Eastern (MID)

AF:

0.00615

AC:

AN:

1138

European-Non Finnish (NFE)

AF:

0.0269

AC:

4182

AN:

155488

Other (OTH)

AF:

0.0220

AC:

305

AN:

13844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

287

574

860

1147

1434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0183

AC:

2782

AN:

152114

Hom.:

Cov.:

AF XY:

0.0193

AC XY:

1433

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00395

AC:

164

AN:

41500

American (AMR)

AF:

0.00726

AC:

111

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00520

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0568

AC:

601

AN:

10584

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0266

AC:

1810

AN:

67992

Other (OTH)

AF:

0.0128

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

147

294

441

588

735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0237

Hom.:

Bravo

AF:

0.0140

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.1

(source)

DANN

Benign

0.71

PhyloP100

0.86

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over