chr9-136676960-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_006412.4(AGPAT2):c.492+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000168 in 1,490,686 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
Genomes: 𝑓 0.000027 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
AGPAT2
NM_006412.4 splice_donor
NM_006412.4 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.30
Genes affected
AGPAT2 (HGNC:325): (1-acylglycerol-3-phosphate O-acyltransferase 2) This gene encodes a member of the 1-acylglycerol-3-phosphate O-acyltransferase family. The protein is located within the endoplasmic reticulum membrane and converts lysophosphatidic acid to phosphatidic acid, the second step in de novo phospholipid biosynthesis. Mutations in this gene have been associated with congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, a disease characterized by a near absence of adipose tissue and severe insulin resistance. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.7, offset of 23, new splice context is: tcgGTgggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 9-136676960-C-T is Pathogenic according to our data. Variant chr9-136676960-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGPAT2 | NM_006412.4 | c.492+1G>A | splice_donor_variant | ENST00000371696.7 | |||
AGPAT2 | NM_001012727.2 | c.492+1G>A | splice_donor_variant | ||||
AGPAT2 | XM_047422636.1 | c.183+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGPAT2 | ENST00000371696.7 | c.492+1G>A | splice_donor_variant | 1 | NM_006412.4 | P1 | |||
AGPAT2 | ENST00000371694.7 | c.492+1G>A | splice_donor_variant | 1 | |||||
AGPAT2 | ENST00000472820.1 | n.420+1G>A | splice_donor_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000268 AC: 4AN: 149404Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000162 AC: 4AN: 247676Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134670
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GnomAD4 exome AF: 0.0000157 AC: 21AN: 1341282Hom.: 0 Cov.: 39 AF XY: 0.0000135 AC XY: 9AN XY: 666060
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GnomAD4 genome AF: 0.0000268 AC: 4AN: 149404Hom.: 0 Cov.: 32 AF XY: 0.0000274 AC XY: 2AN XY: 72934
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital generalized lipodystrophy type 1 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The variant is reported with the allele frequency of 0.001615% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar as Pathogenic. The variant affects an invariant splice nucleotide and is expected to cause loss of function. Downstream loss of function variants have been reported to be disease causing. The nucleotide change in AGPAT2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 20301391, 32041611, 14557463) - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 13
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at