rs142993240

Positions:

• chr9-136676978-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000371696.7(AGPAT2):​c.475C>T​(p.Arg159Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00516 in 1,570,472 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (30 hom.)
• Consequence: AGPAT2 ENST00000371696.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 2.85

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013234198).
• BP6: Variant 9-136676978-G-A is Benign according to our data. Variant chr9-136676978-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210105.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=1, Uncertain_significance=1, Uncertain_risk_allele=1}. Variant chr9-136676978-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00451 (671/148876) while in subpopulation SAS AF= 0.00814 (37/4548). AF 95% confidence interval is 0.00607. There are 6 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGPAT2	NM_006412.4	c.475C>T	p.Arg159Cys	missense_variant	3/6	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2	c.475C>T	p.Arg159Cys	missense_variant	3/5		NP_001012745.1
AGPAT2	XM_047422636.1	c.166C>T	p.Arg56Cys	missense_variant	3/6		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGPAT2	ENST00000371696.7	c.475C>T	p.Arg159Cys	missense_variant	3/6	1	NM_006412.4	ENSP00000360761	P1
AGPAT2	ENST00000371694.7	c.475C>T	p.Arg159Cys	missense_variant	3/5	1		ENSP00000360759
AGPAT2	ENST00000472820.1	n.403C>T		non_coding_transcript_exon_variant	1/4	1
AGPAT2	ENST00000470861.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 671 AN: 148742 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00568

Gnomad ASJ AF: 0.0102

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00814

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00621

Gnomad OTH AF: 0.00824

GnomAD3 exomes AF: 0.00514 AC: 1277 AN: 248240 Hom.: 9 AF XY: 0.00561 AC XY: 756 AN XY: 134796

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.00498

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00715

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00624

Gnomad OTH exome AF: 0.00918

GnomAD4 exome AF: 0.00523 AC: 7438 AN: 1421596 Hom.: 30 Cov.: 38 AF XY: 0.00541 AC XY: 3823 AN XY: 706970

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00745

Gnomad4 FIN exome AF: 0.00207

Gnomad4 NFE exome AF: 0.00524

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.00451 AC: 671 AN: 148876 Hom.: 6 Cov.: 32 AF XY: 0.00450 AC XY: 327 AN XY: 72600

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00567

Gnomad4 ASJ AF: 0.0102

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00814

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00621

Gnomad4 OTH AF: 0.00815

Alfa AF: 0.00642 Hom.: 4

Bravo AF: 0.00459

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00545 AC: 661

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	AGPAT2: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 30, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 19, 2022	Variant summary: AGPAT2 c.475C>T (p.Arg159Cys) results in a non-conservative amino acid change located in the Phospholipid/glycerol acyltransferase domain (IPR002123) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0051 in 248240 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 5.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in AGPAT2 causing Congenital Generalized Lipodystrophy phenotype (0.00087), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Congenital generalized lipodystrophy type 1 Benign:1 Other:1

Uncertain risk allele, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in AGPAT2 gene are associated with Congenital generalized lipodystrophy, type 1, which can present with insulin resistance, fatty liver and diabetes. rs142993240 variant is prevalent with Congenital Generalized Lipoatrophy. However, the role of this rs142993240 particular variant is yet to be ascertained. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

AGPAT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 22, 2019

ACMG criteria: BS1 (1% in gnomAD AJ population, 0.5% overall MAF in gnomAD; disease prevalence 1:10 million gives MAF of 0.03%), BS2 (8 homozygotes in gnomAD) [REVEL 0.582, BP4 (3 predictors), PP3 (6 predictors)= conflicting evidence, not using]; heterozygotes mutation found in brother and sister with lipodytrophy phenotype Simsir et al. 2015 ""Heterozygous AGPAT2 Mutation, Diabetes, and Lipodystrophy in Extremities"" (no PMID)= benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.040	D;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.33
MVP		0.99
MPC		0.68
ClinPred		0.015	T
GERP RS		2.7
Varity_R		0.28
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs142993240; hg19: chr9-139571430; COSMIC: COSV58246892; COSMIC: COSV58246892;