rs121908050
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000229.2(LCAT):c.440C>T(p.Thr147Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,612,762 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
LCAT
NM_000229.2 missense
NM_000229.2 missense
Scores
8
10
1
Clinical Significance
Conservation
PhyloP100: 5.80
Genes affected
LCAT (HGNC:6522): (lecithin-cholesterol acyltransferase) This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.923
PP5
?
Variant 16-67942754-G-A is Pathogenic according to our data. Variant chr16-67942754-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-67942754-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LCAT | NM_000229.2 | c.440C>T | p.Thr147Ile | missense_variant | 4/6 | ENST00000264005.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LCAT | ENST00000264005.10 | c.440C>T | p.Thr147Ile | missense_variant | 4/6 | 1 | NM_000229.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249582Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135334
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GnomAD4 exome AF: 0.0000644 AC: 94AN: 1460546Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 39AN XY: 726580
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 147 of the LCAT protein (p.Thr147Ile). This variant is present in population databases (rs121908050, gnomAD 0.009%). This missense change has been observed in individual(s) with Fish-eye disease (PMID: 1588268, 2052566, 21901787). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr123Ile. ClinVar contains an entry for this variant (Variation ID: 3660). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LCAT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LCAT function (PMID: 25948084). For these reasons, this variant has been classified as Pathogenic. - |
Norum disease;C0342895:Fish-eye disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 04, 2022 | - - |
Fish-eye disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1992 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at