9-136677118-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_006412.4(AGPAT2):c.335C>T(p.Pro112Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,460,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006412.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AGPAT2 | NM_006412.4 | c.335C>T | p.Pro112Leu | missense_variant | Exon 3 of 6 | ENST00000371696.7 | NP_006403.2 | |
AGPAT2 | NM_001012727.2 | c.335C>T | p.Pro112Leu | missense_variant | Exon 3 of 5 | NP_001012745.1 | ||
AGPAT2 | XM_047422636.1 | c.26C>T | p.Pro9Leu | missense_variant | Exon 3 of 6 | XP_047278592.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AGPAT2 | ENST00000371696.7 | c.335C>T | p.Pro112Leu | missense_variant | Exon 3 of 6 | 1 | NM_006412.4 | ENSP00000360761.2 | ||
AGPAT2 | ENST00000371694.7 | c.335C>T | p.Pro112Leu | missense_variant | Exon 3 of 5 | 1 | ENSP00000360759.3 | |||
AGPAT2 | ENST00000472820.1 | n.263C>T | non_coding_transcript_exon_variant | Exon 1 of 4 | 1 | |||||
AGPAT2 | ENST00000470861.1 | n.629C>T | non_coding_transcript_exon_variant | Exon 2 of 2 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247618Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134570
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1460758Hom.: 0 Cov.: 37 AF XY: 0.0000110 AC XY: 8AN XY: 726672
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Congenital generalized lipodystrophy type 1 Uncertain:1Other:1
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The AGPAT2 c.335C>T (p.Pro112Leu) variant is a missense variant that has been reported in three studies, where it was found in a total of three individuals with Berardinelli-Seip congenital lipodystrophy. It was found in a homozygous state in two individuals and in a compound heterozygous state in one. It was also found in a heterozygous state in two unaffected relatives (Taleban et al. 2008; Turkia et al. 2009; Pelosini et al. 2011). The p.Pro112Leu variant was absent from 118 controls and is not found in the 1000 Genomes Project, Exome Sequencing Project or Exome Aggregation Consortium despite being located in a region of good sequencing coverage. Therefore, the variant is presumed to be rare. Peripheral blood mononuclear cell assays showed a reduction in AGPAT2 activity by 70% in a patient who was compound heterozygous for the p.Pro112Leu variant and another variant compared to the activity in controls (Taleban et al. 2008). The evidence for this variant is limited. The p.Pro112Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for Berardinelli-Seip congenital lipodystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19026526, 21744063, 32924125, 18640396) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at