15-96326353-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_001145155.2(NR2F2):c.43+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000186 in 1,612,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_001145155.2 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NR2F2 | NM_001145155.2 | c.43+1G>A | splice_donor_variant, intron_variant | Intron 1 of 2 | NP_001138627.1 | |||
NR2F2-AS1 | NR_102743.1 | n.163+846C>T | intron_variant | Intron 1 of 7 | ||||
NR2F2-AS1 | NR_102744.1 | n.163+846C>T | intron_variant | Intron 1 of 1 | ||||
NR2F2-AS1 | NR_125738.1 | n.163+603C>T | intron_variant | Intron 1 of 4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NR2F2 | ENST00000421109.6 | c.43+1G>A | splice_donor_variant, intron_variant | Intron 1 of 2 | 1 | ENSP00000401674.2 | ||||
NR2F2-AS1 | ENST00000561344.5 | n.150+846C>T | intron_variant | Intron 1 of 6 | 1 | |||||
NR2F2-AS1 | ENST00000502125.6 | n.163+846C>T | intron_variant | Intron 1 of 5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460434Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726636
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
not provided Uncertain:1
The c.43+1G>A variant in the NR2F2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.43+1G>A splice site variant destroys the canonical splice donor site in intron 1. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, this variant occurs in an alternate transcript of NR2F2 where no disease-associated variants have been reported. We interpret c.43+1G>A as variant of uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at