9-136673535-C-T

Variant names:

• chr9-136673535-C-T
• rs886063720
• NM_006412.4:c.*217G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006412.4(AGPAT2):​c.*217G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 426,148 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 0.000023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: AGPAT2 NM_006412.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0960
• Publications: 0 publications found

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]

AGPAT2 Gene-Disease associations (from GenCC):

• congenital generalized lipodystrophy type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• lipodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal diabetes mellitus

  Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006412.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPAT2	NM_006412.4	MANE Select	c.*217G>A		3_prime_UTR	Exon 6 of 6	NP_006403.2
	AGPAT2	NM_001012727.2		c.*217G>A		3_prime_UTR	Exon 5 of 5	NP_001012745.1	O15120-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGPAT2	ENST00000371696.7	TSL:1 MANE Select	c.*217G>A		3_prime_UTR	Exon 6 of 6	ENSP00000360761.2	O15120-1
	AGPAT2	ENST00000371694.7	TSL:1	c.*217G>A		3_prime_UTR	Exon 5 of 5	ENSP00000360759.3	O15120-2
	AGPAT2	ENST00000951406.1		c.*217G>A		3_prime_UTR	Exon 6 of 6	ENSP00000621465.1

Frequencies

GnomAD3 genomes AF: 0.0000233 AC: 3 AN: 128526 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000168 AC: 5 AN: 297622 Hom.: 0 Cov.: 5 AF XY: 0.0000132 AC XY: 2 AN XY: 151992

African (AFR) AF: 0.00 AC: 0 AN: 7788

American (AMR) AF: 0.00 AC: 0 AN: 7556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9804

East Asian (EAS) AF: 0.00 AC: 0 AN: 22734

South Asian (SAS) AF: 0.00 AC: 0 AN: 10684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1412

European-Non Finnish (NFE) AF: 0.0000254 AC: 5 AN: 196912

Other (OTH) AF: 0.00 AC: 0 AN: 18198

GnomAD4 genome AF: 0.0000233 AC: 3 AN: 128526 Hom.: 0 Cov.: 32 AF XY: 0.0000159 AC XY: 1 AN XY: 62992

African (AFR) AF: 0.00 AC: 0 AN: 39088

American (AMR) AF: 0.000158 AC: 2 AN: 12648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2340

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 220

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53332

Other (OTH) AF: 0.00 AC: 0 AN: 1614

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital generalized lipodystrophy type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.68
PhyloP100		-0.096

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

Other links and lift over

dbSNP: rs886063720; hg19: chr9-139567987;