9-136673520-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006412.4(AGPAT2):c.*232C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 421,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: AGPAT2 NM_006412.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.335

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGPAT2	NM_006412.4	c.*232C>T		3_prime_UTR_variant	6/6	ENST00000371696.7
AGPAT2	NM_001012727.2	c.*232C>T		3_prime_UTR_variant	5/5
AGPAT2	XM_047422636.1	c.*232C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPAT2	ENST00000371696.7	c.*232C>T		3_prime_UTR_variant	6/6	1	NM_006412.4	P1
AGPAT2	ENST00000371694.7	c.*232C>T		3_prime_UTR_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.000528 AC: 80 AN: 151638 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000694

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.000393 AC: 106 AN: 269930 Hom.: 0 Cov.: 4 AF XY: 0.000419 AC XY: 58 AN XY: 138492

Gnomad4 AFR exome AF: 0.000819

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000406

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000455

Gnomad4 NFE exome AF: 0.000457

Gnomad4 OTH exome AF: 0.000640

GnomAD4 genome AF: 0.000527 AC: 80 AN: 151756 Hom.: 0 Cov.: 34 AF XY: 0.000472 AC XY: 35 AN XY: 74174

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000695

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.000688 Hom.: 0

Bravo AF: 0.000495

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital generalized lipodystrophy type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.2
Dann	Benign	0.57

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: rs573498539; hg19: chr9-139567972;