chr9-136677118-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

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

AGPAT2
NM_006412.4 missense

Scores

11
7
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 8.92
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 9-136677118-G-A is Pathogenic according to our data. Variant chr9-136677118-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 365928.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AGPAT2NM_006412.4 linkc.335C>T p.Pro112Leu missense_variant Exon 3 of 6 ENST00000371696.7 NP_006403.2 O15120-1A0A024R8I7
AGPAT2NM_001012727.2 linkc.335C>T p.Pro112Leu missense_variant Exon 3 of 5 NP_001012745.1 O15120-2A0A024R8F9
AGPAT2XM_047422636.1 linkc.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
AGPAT2ENST00000371696.7 linkc.335C>T p.Pro112Leu missense_variant Exon 3 of 6 1 NM_006412.4 ENSP00000360761.2 O15120-1
AGPAT2ENST00000371694.7 linkc.335C>T p.Pro112Leu missense_variant Exon 3 of 5 1 ENSP00000360759.3 O15120-2
AGPAT2ENST00000472820.1 linkn.263C>T non_coding_transcript_exon_variant Exon 1 of 4 1
AGPAT2ENST00000470861.1 linkn.629C>T non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000404
AC:
1
AN:
247618
Hom.:
0
AF XY:
0.00000743
AC XY:
1
AN XY:
134570
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1460758
Hom.:
0
Cov.:
37
AF XY:
0.0000110
AC XY:
8
AN XY:
726672
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Sep 12, 2023
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Congenital generalized lipodystrophy type 1 Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
.;D;D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.94
D;.;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.4
M;M;M
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-8.5
D;D;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.024
D;T;T
Polyphen
1.0
D;D;D
Vest4
0.97
MutPred
0.88
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP
0.98
MPC
0.61
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.80
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886063722; hg19: chr9-139571570; COSMIC: COSV58247933; COSMIC: COSV58247933; API