rs138994150

chr9-136674750-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_006412.4(AGPAT2):c.646A>T(p.Lys216Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,510,710 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: 𝑓 0.00094 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: AGPAT2 NM_006412.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 B:1 O:1
• Conservation: PhyloP100: 2.26

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGPAT2	NM_006412.4	c.646A>T	p.Lys216Ter	stop_gained	5/6	ENST00000371696.7
AGPAT2	NM_001012727.2	c.550A>T	p.Lys184Ter	stop_gained	4/5
AGPAT2	XM_047422636.1	c.337A>T	p.Lys113Ter	stop_gained	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPAT2	ENST00000371696.7	c.646A>T	p.Lys216Ter	stop_gained	5/6	1	NM_006412.4	P1
AGPAT2	ENST00000371694.7	c.550A>T	p.Lys184Ter	stop_gained	4/5	1
AGPAT2	ENST00000472820.1	n.574A>T		non_coding_transcript_exon_variant	3/4	1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000396 AC: 71 AN: 179484 Hom.: 0 AF XY: 0.000339 AC XY: 33 AN XY: 97348

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.000165

Gnomad EAS exome AF: 0.00123

Gnomad SAS exome AF: 0.000321

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.000140 AC: 190 AN: 1358432 Hom.: 0 Cov.: 30 AF XY: 0.000142 AC XY: 95 AN XY: 669302

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.000154

Gnomad4 ASJ exome AF: 0.0000455

Gnomad4 EAS exome AF: 0.000498

Gnomad4 SAS exome AF: 0.000436

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 0.0000350

Gnomad4 OTH exome AF: 0.000286

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74470

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000503 Hom.: 0

Bravo AF: 0.00119

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000422 AC: 51

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital generalized lipodystrophy type 1 Pathogenic:3 Uncertain:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The AGPAT2 c.646A>T (p.Lys216Ter) variant is a stop-gained variant that is predicted to cause premature truncation of the protein. This variant has been reported in two studies in which it is found in a total of two individuals with Berardinelli-Seip congenital lipodystrophy, both of whom were homozygous for the variant (Marge et al. 2003; Akinci et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00454 in the African population of the 1000 Genomes Project. Due to the potential impact of stop-gained variants and the limited evidence, this 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The stop gained c.646A>T(p.Lys216Ter) variant in AGPAT2 gene has been reported previously in homozygous state in individual(s) affected with Berardinelli-Seip congenital lipodystrophy (Akinci B, et. al.,2016; Magré J, et. al., 2003). The c.646A>T variant has been reported with allele frequency of 0.04% in gnomAD Exomes databases. This variant has been reported to the ClinVar database as Likely Benign/ Uncertain Significance / Likely Pathogenic / Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	39
Dann	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.038
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;D;D
Vest4		0.71
GERP RS		3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs138994150; hg19: chr9-139569202;