rs104894100

Positions:

• chr9-136673906-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006412.4(AGPAT2):​c.683T>C​(p.Leu228Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000347 in 1,439,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: AGPAT2 NM_006412.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.90

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 9-136673906-A-G is Pathogenic according to our data. Variant chr9-136673906-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6627.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGPAT2	NM_006412.4	c.683T>C	p.Leu228Pro	missense_variant	6/6	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2	c.587T>C	p.Leu196Pro	missense_variant	5/5		NP_001012745.1
AGPAT2	XM_047422636.1	c.374T>C	p.Leu125Pro	missense_variant	6/6		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGPAT2	ENST00000371696.7	c.683T>C	p.Leu228Pro	missense_variant	6/6	1	NM_006412.4	ENSP00000360761.2
AGPAT2	ENST00000371694.7	c.587T>C	p.Leu196Pro	missense_variant	5/5	1		ENSP00000360759.3
AGPAT2	ENST00000472820.1	n.611T>C		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1439674 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714546

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000454

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital generalized lipodystrophy type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T;.;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H;H
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.93
MutPred		0.93		.;Gain of disorder (P = 0.033);Gain of disorder (P = 0.033);
MVP		0.99
MPC		0.86
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.83
gMVP		0.98

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: rs104894100; hg19: chr9-139568358;