rs114782902

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP3BP4_StrongBP6BS1

The NM_006412.4(AGPAT2):c.359A>G(p.Lys120Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000308 in 1,613,152 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

AGPAT2
NM_006412.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 7.14

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 Likely_benign. Variant got -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.046096176).

BP6

Variant 9-136677094-T-C is Benign according to our data. Variant chr9-136677094-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393425.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00149 (227/152260) while in subpopulation AFR AF= 0.00513 (213/41544). AF 95% confidence interval is 0.00456. There are 1 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AGPAT2	NM_006412.4 linkuse as main transcript	c.359A>G	p.Lys120Arg	missense_variant	3/6	ENST00000371696.7
AGPAT2	NM_001012727.2 linkuse as main transcript	c.359A>G	p.Lys120Arg	missense_variant	3/5
AGPAT2	XM_047422636.1 linkuse as main transcript	c.50A>G	p.Lys17Arg	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPAT2	ENST00000371696.7 linkuse as main transcript	c.359A>G	p.Lys120Arg	missense_variant	3/6	1	NM_006412.4	P1	O15120-1
AGPAT2	ENST00000371694.7 linkuse as main transcript	c.359A>G	p.Lys120Arg	missense_variant	3/5	1			O15120-2
AGPAT2	ENST00000472820.1 linkuse as main transcript	n.287A>G		non_coding_transcript_exon_variant	1/4	1
AGPAT2	ENST00000470861.1 linkuse as main transcript	n.653A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

227

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00514

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000342

AC:

AN:

248480

Hom.:

AF XY:

0.000274

AC XY:

AN XY:

134820

show subpopulations

Gnomad AFR exome

AF:

0.00489

Gnomad AMR exome

AF:

0.000145

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:

0.000164

GnomAD4 exome

AF:

0.000185

AC:

270

AN:

1460892

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.00732

Gnomad4 AMR exome

AF:

0.000179

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:

0.00000360

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.00149

AC:

227

AN:

152260

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00513

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000387

Hom.:

Bravo

AF:

0.00168

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2023	BS1, PP3 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 08, 2023

Variant summary: AGPAT2 c.359A>G (p.Lys120Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 248480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AGPAT2 causing Congenital Generalized Lipodystrophy (0.00034 vs 0.00087), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.359A>G in individuals affected with Congenital Generalized Lipodystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 19, 2016

ACMG Criteria: PP3 -

Congenital generalized lipodystrophy type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 22, 2022

- -

AGPAT2-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2023

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.48

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;.;D

MetaRNN

Benign

0.046

T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Pathogenic

3.3

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.024

D;T;T

Polyphen

1.0

D;D;D

Vest4

0.91

MVP

0.94

MPC

0.61

ClinPred

0.10

GERP RS

4.8

Varity_R

0.86

gMVP

0.93

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.

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