NM_013251.4:c.209-1G>C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_013251.4(TAC3):c.209-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000589 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_013251.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TAC3 | NM_013251.4 | c.209-1G>C | splice_acceptor_variant, intron_variant | Intron 3 of 6 | ENST00000458521.7 | NP_037383.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TAC3 | ENST00000458521.7 | c.209-1G>C | splice_acceptor_variant, intron_variant | Intron 3 of 6 | 1 | NM_013251.4 | ENSP00000404056.2 | |||
TAC3 | ENST00000300108.7 | n.209-1G>C | splice_acceptor_variant, intron_variant | Intron 3 of 8 | 2 | ENSP00000300108.3 | ||||
TAC3 | ENST00000379411.6 | n.209-1G>C | splice_acceptor_variant, intron_variant | Intron 3 of 7 | 2 | ENSP00000368721.2 | ||||
TAC3 | ENST00000393867.5 | n.209-1G>C | splice_acceptor_variant, intron_variant | Intron 3 of 9 | 2 | ENSP00000377445.1 |
Frequencies
GnomAD3 genomes AF: 0.000348 AC: 53AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000994 AC: 25AN: 251452Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135904
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461790Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727200
GnomAD4 genome AF: 0.000348 AC: 53AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74454
ClinVar
Submissions by phenotype
not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individuals with Idiopathic hypogonadotropic hypogonadism (PMID: 20194706, 31200363). This variant is present in population databases (rs146391497, gnomAD 0.1%). This sequence change affects an acceptor splice site in intron 3 of the TAC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TAC3 are known to be pathogenic (PMID: 20194706, 20332248, 25077900). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at