9-136673310-G-C

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.*442C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 156,518 control chromosomes in the GnomAD database, including 45,945 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.76 (44556 hom., cov: 34)
  • Exomes 𝑓: 0.80 (1389 hom.)
• Consequence: AGPAT2 NM_006412.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.299

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=-0.87).
• BP6: Variant 9-136673310-G-C is Benign according to our data. Variant chr9-136673310-G-C is described in ClinVar as [Benign]. Clinvar id is 365904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGPAT2	NM_006412.4	c.*442C>G		3_prime_UTR_variant	6/6	ENST00000371696.7
AGPAT2	NM_001012727.2	c.*442C>G		3_prime_UTR_variant	5/5
AGPAT2	XM_047422636.1	c.*442C>G		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPAT2	ENST00000371696.7	c.*442C>G		3_prime_UTR_variant	6/6	1	NM_006412.4	P1
AGPAT2	ENST00000371694.7	c.*442C>G		3_prime_UTR_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115800 AN: 152068 Hom.: 44554 Cov.: 34

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.862

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.942

Gnomad SAS AF: 0.894

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.756

GnomAD4 exome AF: 0.796 AC: 3449 AN: 4332 Hom.: 1389 Cov.: 0 AF XY: 0.792 AC XY: 1727 AN XY: 2180

Gnomad4 AFR exome AF: 0.646

Gnomad4 AMR exome AF: 0.745

Gnomad4 ASJ exome AF: 0.799

Gnomad4 EAS exome AF: 0.956

Gnomad4 SAS exome AF: 0.946

Gnomad4 FIN exome AF: 0.759

Gnomad4 NFE exome AF: 0.797

Gnomad4 OTH exome AF: 0.788

GnomAD4 genome AF: 0.761 AC: 115838 AN: 152186 Hom.: 44556 Cov.: 34 AF XY: 0.765 AC XY: 56910 AN XY: 74380

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.810

Gnomad4 ASJ AF: 0.785

Gnomad4 EAS AF: 0.942

Gnomad4 SAS AF: 0.893

Gnomad4 FIN AF: 0.794

Gnomad4 NFE AF: 0.788

Gnomad4 OTH AF: 0.752

Alfa AF: 0.772 Hom.: 5666

Bravo AF: 0.756

Asia WGS AF: 0.891 AC: 3098 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	-0.87
Cadd	Benign	14
Dann	Benign	0.75

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: rs6951; hg19: chr9-139567762;