NM_006412.4:c.493-1G>C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_006412.4(AGPAT2):c.493-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000186 in 1,613,232 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 Likely pathogenic (★★).
Frequency
Consequence
NM_006412.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AGPAT2 | NM_006412.4 | c.493-1G>C | splice_acceptor_variant, intron_variant | Intron 3 of 5 | ENST00000371696.7 | NP_006403.2 | ||
AGPAT2 | NM_001012727.2 | c.492+280G>C | intron_variant | Intron 3 of 4 | NP_001012745.1 | |||
AGPAT2 | XM_047422636.1 | c.184-1G>C | splice_acceptor_variant, intron_variant | Intron 3 of 5 | XP_047278592.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AGPAT2 | ENST00000371696.7 | c.493-1G>C | splice_acceptor_variant, intron_variant | Intron 3 of 5 | 1 | NM_006412.4 | ENSP00000360761.2 | |||
AGPAT2 | ENST00000371694.7 | c.492+280G>C | intron_variant | Intron 3 of 4 | 1 | ENSP00000360759.3 | ||||
AGPAT2 | ENST00000472820.1 | n.421-1G>C | splice_acceptor_variant, intron_variant | Intron 1 of 3 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250564Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135758
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461024Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726808
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Congenital generalized lipodystrophy type 1 Pathogenic:3Other:1
The c.493-1G>C variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 6630; PMID: 24498038, 15181077) - PS4_supporting. The variant is present at low allele frequencies population databases (rs606231168 – gnomAD 0.00006570%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.493-1G>C was detected in trans with a pathogenic variant (PMID: 24498038) - PM3. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at