rs142417583

Positions:

• chr9-136673780-G-A

Variant summary

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

The NM_006412.4(AGPAT2):​c.809C>T​(p.Ala270Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,602,004 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (10 hom., cov: 34)
  • Exomes 𝑓: 0.00064 (8 hom.)
• Consequence: AGPAT2 NM_006412.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.58

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=0.003097862).
• BP6: Variant 9-136673780-G-A is Benign according to our data. Variant chr9-136673780-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393423.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00593 (904/152352) while in subpopulation AFR AF= 0.0207 (862/41580). AF 95% confidence interval is 0.0196. There are 10 homozygotes in gnomad4. There are 412 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGPAT2	NM_006412.4	c.809C>T	p.Ala270Val	missense_variant	6/6	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2	c.713C>T	p.Ala238Val	missense_variant	5/5		NP_001012745.1
AGPAT2	XM_047422636.1	c.500C>T	p.Ala167Val	missense_variant	6/6		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGPAT2	ENST00000371696.7	c.809C>T	p.Ala270Val	missense_variant	6/6	1	NM_006412.4	ENSP00000360761	P1
AGPAT2	ENST00000371694.7	c.713C>T	p.Ala238Val	missense_variant	5/5	1		ENSP00000360759
AGPAT2	ENST00000472820.1	n.737C>T		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 893 AN: 152234 Hom.: 8 Cov.: 34

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00153 AC: 358 AN: 233330 Hom.: 5 AF XY: 0.000997 AC XY: 126 AN XY: 126434

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.0000351

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000711

GnomAD4 exome AF: 0.000639 AC: 926 AN: 1449652 Hom.: 8 Cov.: 31 AF XY: 0.000524 AC XY: 377 AN XY: 720058

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.000690

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000763

Gnomad4 SAS exome AF: 0.0000475

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000307

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.00593 AC: 904 AN: 152352 Hom.: 10 Cov.: 34 AF XY: 0.00553 AC XY: 412 AN XY: 74496

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00312 Hom.: 5

Bravo AF: 0.00660

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00197 AC: 237

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital generalized lipodystrophy type 1 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, 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. However, the role of this particular variant rs142417583 in Congenital generalized lipodystrophy is yet to be ascertained. -

Monogenic diabetes Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Oct 27, 2015

ACMG Criteria: BS2 (type2diabetesgenetics.org), BP4 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.8
DANN	Benign	0.59
DEOGEN2	Benign	0.13	.;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.52	T;.;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.49	.;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.019	B;B;B
Vest4		0.053
MVP		0.58
MPC		0.16
ClinPred		0.0020	T
GERP RS		-7.7
Varity_R		0.022
gMVP		0.46

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

Other links and lift over

dbSNP: rs142417583; hg19: chr9-139568232; COSMIC: COSV99056769; COSMIC: COSV99056769;