rs116807569

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_006412.4(AGPAT2):c.589-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000724 in 1,546,742 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

AGPAT2
NM_006412.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 2.08

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]

AGPAT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08721625 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of -33, new splice context is: tgtgcctggcctgtccccAGggc. Cryptic site results in inframe 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;

PP5

Variant 9-136674809-T-C is Pathogenic according to our data. Variant chr9-136674809-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 6625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AGPAT2	NM_006412.4 link	c.589-2A>G	splice_acceptor_variant, intron_variant	Intron 4 of 5	ENST00000371696.7	NP_006403.2	O15120-1A0A024R8I7
AGPAT2	NM_001012727.2 link	c.493-2A>G	splice_acceptor_variant, intron_variant	Intron 3 of 4		NP_001012745.1	O15120-2A0A024R8F9
AGPAT2	XM_047422636.1 link	c.280-2A>G	splice_acceptor_variant, intron_variant	Intron 4 of 5		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
AGPAT2	ENST00000371696.7 link	c.589-2A>G	splice_acceptor_variant, intron_variant	Intron 4 of 5	1	NM_006412.4	ENSP00000360761.2	O15120-1
AGPAT2	ENST00000371694.7 link	c.493-2A>G	splice_acceptor_variant, intron_variant	Intron 3 of 4	1		ENSP00000360759.3	O15120-2
AGPAT2	ENST00000472820.1 link	n.517-2A>G	splice_acceptor_variant, intron_variant	Intron 2 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000101

AC:

AN:

198966

Hom.:

AF XY:

0.0000645

AC XY:

AN XY:

108540

show subpopulations

Gnomad AFR exome

AF:

0.00140

Gnomad AMR exome

AF:

0.0000787

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:

0.0000359

AC:

AN:

1394460

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

690884

show subpopulations

Gnomad4 AFR exome

AF:

0.00145

Gnomad4 AMR exome

AF:

0.0000550

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.0000348

GnomAD4 genome

AF:

0.000407

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000784

Hom.:

Bravo

AF:

0.000419

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital generalized lipodystrophy type 1

Pathogenic:4Other:1

Aug 03, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The AGPAT2 c.589-2A>G variant, also referred to as IVS4-2A>G, results a substitution within the consensus splice acceptor site. This variant is predicted to result in a frameshift and premature termination with addition of novel amino acids (PMID: 11967537; 12765973). The c.589-2A>G variant has been reported in at least 24 unrelated individuals in a homozygous state and at least 11 unrelated individuals in either a confirmed or presumed compound heterozygous state with phenotypes consistent with congenital generalized lipodystrophy (PMID: 11967537; 12765973; 14557463; 31416577; 32280377; 34318892). This variant segregated with disease in multiple families (PMID: 11967537; 12765973 14557463). The c.589-2A>G variant is reported at a frequency of 0.001496 in the African/African American population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, the c.589-2A>G variant is classified as pathogenic for congenital generalized lipodystrophy. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Mar 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30266686, 11967537, 25525159, 19278620, 26072926, 22344438, 15181077, 32041611, 12765973, 32280377, SchweisbergerC2021[Abstract], 34033296, 31416577, 30296183, 30595509, 34318892) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 4 of the AGPAT2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AGPAT2 are known to be pathogenic (PMID: 11967537, 15181077). This variant is present in population databases (rs116807569, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with congenital generalized lipodystrophy (PMID: 11967537, 32876150). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6625). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Congenital generalized lipodystrophy

Pathogenic:1

Dec 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AGPAT2 c.589-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. The variant allele was found at a frequency of 0.0001 in 198966 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AGPAT2 causing Congenital Generalized Lipodystrophy (0.0001 vs 0.00087), allowing no conclusion about variant significance. c.589-2A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Generalized Lipodystrophy (examples: Agarwal_2002 and Magre_2003). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11967537, 12765973). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.80

Position offset: 31

DS_AL_spliceai

1.0

Position offset: -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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over