chr22-43924017-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_025225.3(PNPLA3):​c.106C>A​(p.Leu36Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,583,814 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000091 ( 0 hom. )

Consequence

PNPLA3
NM_025225.3 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.649
Variant links:
Genes affected
PNPLA3 (HGNC:18590): (patatin like phospholipase domain containing 3) The protein encoded by this gene is a triacylglycerol lipase that mediates triacylglycerol hydrolysis in adipocytes. The encoded protein, which appears to be membrane bound, may be involved in the balance of energy usage/storage in adipocytes. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2731737).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PNPLA3NM_025225.3 linkuse as main transcriptc.106C>A p.Leu36Ile missense_variant 1/9 ENST00000216180.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PNPLA3ENST00000216180.8 linkuse as main transcriptc.106C>A p.Leu36Ile missense_variant 1/91 NM_025225.3 P1Q9NST1-1
PNPLA3ENST00000423180.2 linkuse as main transcriptc.106C>A p.Leu36Ile missense_variant 1/92 Q9NST1-2
PNPLA3ENST00000406117.6 linkuse as main transcriptc.106C>A p.Leu36Ile missense_variant, NMD_transcript_variant 1/102

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152250
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000524
AC:
11
AN:
210066
Hom.:
0
AF XY:
0.0000256
AC XY:
3
AN XY:
117352
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000309
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000189
GnomAD4 exome
AF:
0.00000908
AC:
13
AN:
1431446
Hom.:
0
Cov.:
31
AF XY:
0.00000562
AC XY:
4
AN XY:
712356
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152368
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74514
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000252
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 02, 2024The c.106C>A (p.L36I) alteration is located in exon 1 (coding exon 1) of the PNPLA3 gene. This alteration results from a C to A substitution at nucleotide position 106, causing the leucine (L) at amino acid position 36 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.15
T;.
Eigen
Benign
0.081
Eigen_PC
Benign
0.025
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.62
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Benign
-0.42
T
MutationAssessor
Uncertain
2.1
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.4
N;N
REVEL
Uncertain
0.43
Sift
Benign
0.050
D;D
Sift4G
Benign
0.15
T;T
Polyphen
0.98
D;.
Vest4
0.20
MutPred
0.75
Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);
MVP
0.87
MPC
0.42
ClinPred
0.20
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.20
gMVP
0.24

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747966884; hg19: chr22-44319897; API