22-43928847-C-G
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_025225.3(PNPLA3):āc.444C>Gā(p.Ile148Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,605,646 control chromosomes in the GnomAD database, including 47,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars).
Frequency
Consequence
NM_025225.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.228 AC: 34600AN: 151568Hom.: 4559 Cov.: 30
GnomAD3 exomes AF: 0.278 AC: 69773AN: 251130Hom.: 11863 AF XY: 0.267 AC XY: 36253AN XY: 135724
GnomAD4 exome AF: 0.233 AC: 338062AN: 1453960Hom.: 43228 Cov.: 35 AF XY: 0.232 AC XY: 167729AN XY: 723764
GnomAD4 genome AF: 0.228 AC: 34605AN: 151686Hom.: 4560 Cov.: 30 AF XY: 0.233 AC XY: 17303AN XY: 74116
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
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This variant is associated with the following publications: (PMID: 24417250, 26264356, 25273282, 22001757, 25646328, 25290313, 23808989, 25543233, 24828988, 24074360, 24269995, 24102786, 25232397, 30649436, 30802989, 25378656, 30161167, 24009255, 30308089, 29632382, 29083408, 28073161, 28902428, 28950858, 18820647, 22258181, 23042597, 22719190, 24155878, 22100032, 20373368, 22898488, 19946271, 26690388, 21254164, 25678388, 21423719, 20648472, 19738004, 25146957, 20803499, 20546964, 19844213, 22978414, 22878467, 24670599, 24369119, 24972532, 22338072, 22724004, 26200108, 22087248, 25763607, 23023705, 23176674, 23510779, 21168459, 22792295, 24531328, 26439088, 19224197, 19542081, 19729411, 19651814, 21878620, 20034933, 23069476, 22140488, 24081230, 23505555, 26148245, 27346686, 25171251, 25581573, 27346685, 26482880, 28008009) -
PNPLA3: PM1, PP4 -
NAFLD1 Benign:1Other:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
proposed classification - variant undergoing re-assessment, contact laboratory -
Hepatic steatosis Pathogenic:1
The PNPLA3 c.444C>G (p.Ile148Met) variant, has been reported to be a risk allele for nonalcoholic fatty liver disease in adults and youth with an odds ratio of 2.8; 95% CI 1.5-5.2 (Romeo S et al., PMID: 18820647; Santoro N et al., 20803499; Sookoian S et al., PMID: 19738004). The highest population minor allele frequency in the population database genome aggregation database (v2.1.1) is 54.9% in the American population. This variant may increase risk for hepatic steatosis along with other genetic and environmental factors and based on available information and the ClinGen Low Penetrance/Risk Allele Working Group recommendations (Schmidt RJ et al., PMID: 38054408) this variant is classified as a likely risk allele. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at