rs1554754454

Variant names:

• chr9-136677465-A-G
• rs1554754454
• NM_006412.4:c.274T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-136677465-A-G
• chr9-136677465-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006412.4(AGPAT2):​c.274T>C​(p.Cys92Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,768 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGPAT2 NM_006412.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

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.274T>C	p.Cys92Arg	missense	Exon 2 of 6	NP_006403.2
	AGPAT2	NM_001012727.2		c.274T>C	p.Cys92Arg	missense	Exon 2 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.274T>C	p.Cys92Arg	missense	Exon 2 of 6	ENSP00000360761.2	O15120-1
	AGPAT2	ENST00000371694.7	TSL:1	c.274T>C	p.Cys92Arg	missense	Exon 2 of 5	ENSP00000360759.3	O15120-2
	AGPAT2	ENST00000951406.1		c.274T>C	p.Cys92Arg	missense	Exon 2 of 6	ENSP00000621465.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460768 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726710

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	2.0	M
PhyloP100		4.1
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.030	D
Polyphen		0.84	P
Vest4		0.68
MVP		0.97
MPC		0.67
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.90
Mutation Taster		=53/47	polymorphism

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: rs1554754454; hg19: chr9-139571917;