8-19962213-C-G
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1
The NM_000237.3(LPL):āc.1421C>Gā(p.Ser474Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,611,322 control chromosomes in the GnomAD database, including 7,879 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ). Synonymous variant affecting the same amino acid position (i.e. S474S) has been classified as Likely benign.
Frequency
Consequence
NM_000237.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LPL | NM_000237.3 | c.1421C>G | p.Ser474Ter | stop_gained | 9/10 | ENST00000650287.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LPL | ENST00000650287.1 | c.1421C>G | p.Ser474Ter | stop_gained | 9/10 | NM_000237.3 | P1 | ||
LPL | ENST00000650478.1 | c.*244C>G | 3_prime_UTR_variant, NMD_transcript_variant | 3/4 |
Frequencies
GnomAD3 genomes ? AF: 0.0902 AC: 13720AN: 152082Hom.: 611 Cov.: 32
GnomAD3 exomes AF: 0.0922 AC: 23148AN: 251182Hom.: 1212 AF XY: 0.0938 AC XY: 12729AN XY: 135736
GnomAD4 exome AF: 0.0975 AC: 142308AN: 1459122Hom.: 7269 Cov.: 31 AF XY: 0.0979 AC XY: 71091AN XY: 726024
GnomAD4 genome ? AF: 0.0901 AC: 13707AN: 152200Hom.: 610 Cov.: 32 AF XY: 0.0894 AC XY: 6652AN XY: 74408
ClinVar
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2018 | This variant is associated with the following publications: (PMID: 33339817, 8839720, 33111339, 15049943, 28267856, 23050023, 26999119, 26975783, 24974629, 24603370, 28640651, 29687697, 29632382, 29083407, 27516387, 29083408, 27984852, 27535653, 24704550, 26934567, 27055971, 28008009, 2216713, 17029199, 15793775, 21162862, 21816453, 25525159, 24039871, 19148283, 17560523, 19034041, 19664517, 19556723, 18187430, 19368142, 23113749, 25579610, 24176758, 19367320, 19018513, 17291198, 10450862, 17555736, 22244040, 18922999, 19185650) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 16, 2021 | Variant summary: LPL c.1421C>G (p.Ser474X) results in a premature termination two codons before the normal termination codon. The variant allele was found at a frequency of 0.092 in 251182 control chromosomes in the gnomAD database, including 1212 homozygotes. The observed variant frequency is approximately 27-fold of the estimated maximal expected allele frequency for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency phenotype (0.0034), strongly suggesting that the variant is benign. Three ClinVar submitters have assessed this variant since 2014: all have classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Hyperlipoproteinemia, type I Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | 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. - |
LIPOPROTEIN LIPASE POLYMORPHISM Benign:1
Benign, no assertion criteria provided | literature only | OMIM | Jan 15, 1992 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2018 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I Benign:1
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 02, 2022 | - - |
LPL-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 19, 2023 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at