rs1295890527

Variant names:

• chr11-819729-G-A
• rs1295890527
• NM_020376.4:c.11G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-819729-G-A
• chr11-819729-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020376.4(PNPLA2):​c.11G>A​(p.Arg4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,339,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: PNPLA2 NM_020376.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.397
• Publications: 0 publications found

Genes affected

PNPLA2 (HGNC:30802): (patatin like phospholipase domain containing 2) This gene encodes an enzyme which catalyzes the first step in the hydrolysis of triglycerides in adipose tissue. Mutations in this gene are associated with neutral lipid storage disease with myopathy. [provided by RefSeq, Jul 2010]

PNPLA2 Gene-Disease associations (from GenCC):

• neutral lipid storage myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08929467).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020376.4. 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
	PNPLA2	NM_020376.4	MANE Select	c.11G>A	p.Arg4His	missense	Exon 2 of 10	NP_065109.1	Q96AD5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA2	ENST00000336615.9	TSL:1 MANE Select	c.11G>A	p.Arg4His	missense	Exon 2 of 10	ENSP00000337701.4	Q96AD5-1
	PNPLA2	ENST00000869283.1		c.11G>A	p.Arg4His	missense	Exon 2 of 11	ENSP00000539342.1
	PNPLA2	ENST00000869284.1		c.11G>A	p.Arg4His	missense	Exon 2 of 10	ENSP00000539343.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000992 AC: 1 AN: 100852 AF XY: 0.0000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000279

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000299 AC: 4 AN: 1339644 Hom.: 0 Cov.: 32 AF XY: 0.00000455 AC XY: 3 AN XY: 659298

African (AFR) AF: 0.00 AC: 0 AN: 27042

American (AMR) AF: 0.00 AC: 0 AN: 29394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23632

East Asian (EAS) AF: 0.00 AC: 0 AN: 28938

South Asian (SAS) AF: 0.00 AC: 0 AN: 74160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4376

European-Non Finnish (NFE) AF: 0.00000380 AC: 4 AN: 1052616

Other (OTH) AF: 0.00 AC: 0 AN: 55102

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neutral lipid storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.40
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.078
Sift	Benign	0.13	T
Sift4G	Benign	0.13	T
Polyphen		0.94	P
Vest4		0.092
MutPred		0.27		Gain of glycosylation at T7 (P = 0.0696)
MVP		0.25
MPC		2.6
ClinPred		0.54	D
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.076
gMVP		0.12
Mutation Taster		=99/1	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: rs1295890527; hg19: chr11-819729; COSMIC: COSV60744956; COSMIC: COSV60744956;