9-136673235-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006412.4(AGPAT2):c.*517C>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 0.237 in 152,966 control chromosomes in the GnomAD database, including 4,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4832 hom., cov: 34)
  • Exomes 𝑓: 0.19 (21 hom.)
• Consequence: AGPAT2 NM_006412.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.46

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-136673235-G-A is Benign according to our data. Variant chr9-136673235-G-A is described in ClinVar as [Benign]. Clinvar id is 365901.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGPAT2	NM_006412.4	c.*517C>T		3_prime_UTR_variant	6/6	ENST00000371696.7
AGPAT2	NM_001012727.2	c.*517C>T		3_prime_UTR_variant	5/5
AGPAT2	XM_047422636.1	c.*517C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPAT2	ENST00000371696.7	c.*517C>T		3_prime_UTR_variant	6/6	1	NM_006412.4	P1
AGPAT2	ENST00000371694.7	c.*517C>T		3_prime_UTR_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36083 AN: 152056 Hom.: 4815 Cov.: 34

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.298

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.192 AC: 152 AN: 792 Hom.: 21 Cov.: 0 AF XY: 0.196 AC XY: 88 AN XY: 450

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.0455

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.679

Gnomad4 SAS exome AF: 0.0714

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.237 AC: 36119 AN: 152174 Hom.: 4832 Cov.: 34 AF XY: 0.241 AC XY: 17930 AN XY: 74390

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.588

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.207

Gnomad4 OTH AF: 0.233

Alfa AF: 0.218 Hom.: 1295

Bravo AF: 0.241

Asia WGS AF: 0.414 AC: 1440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital generalized lipodystrophy type 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.50
Dann	Benign	0.54

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: rs10320; hg19: chr9-139567687;