chr9-136673673-G-C

Position:

• chr9-136673673-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006412.4(AGPAT2):​c.*79C>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 0.00439 in 1,408,574 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 34)
  • Exomes 𝑓: 0.0027 (68 hom.)
• Consequence: AGPAT2 NM_006412.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.68

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-136673673-G-C is Benign according to our data. Variant chr9-136673673-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 365914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGPAT2	NM_006412.4	c.*79C>G		3_prime_UTR_variant	6/6	ENST00000371696.7
AGPAT2	NM_001012727.2	c.*79C>G		3_prime_UTR_variant	5/5
AGPAT2	XM_047422636.1	c.*79C>G		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGPAT2	ENST00000371696.7	c.*79C>G		3_prime_UTR_variant	6/6	1	NM_006412.4	P1
AGPAT2	ENST00000371694.7	c.*79C>G		3_prime_UTR_variant	5/5	1
AGPAT2	ENST00000472820.1			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2788 AN: 152148 Hom.: 73 Cov.: 34

Gnomad AFR AF: 0.0601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00269 AC: 3377 AN: 1256308 Hom.: 68 Cov.: 21 AF XY: 0.00241 AC XY: 1472 AN XY: 611780

Gnomad4 AFR exome AF: 0.0687

Gnomad4 AMR exome AF: 0.00516

Gnomad4 ASJ exome AF: 0.00830

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000247

Gnomad4 FIN exome AF: 0.000136

Gnomad4 NFE exome AF: 0.000777

Gnomad4 OTH exome AF: 0.00714

GnomAD4 genome AF: 0.0185 AC: 2812 AN: 152266 Hom.: 76 Cov.: 34 AF XY: 0.0179 AC XY: 1330 AN XY: 74454

Gnomad4 AFR AF: 0.0605

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000971

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.000704 Hom.: 0

Bravo AF: 0.0209

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	This variant is associated with the following publications: (PMID: 11967537) -

Congenital generalized lipodystrophy type 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 24, 2021	- -
Benign, 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 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	-0.91
CADD	Benign	0.13
DANN	Benign	0.56

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: rs112657922; hg19: chr9-139568125;