chr4-154744366-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004744.5(LRAT):c.40G>T(p.Glu14Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,032 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 Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
LRAT
NM_004744.5 stop_gained
NM_004744.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 7.33
Genes affected
LRAT (HGNC:6685): (lecithin retinol acyltransferase) The protein encoded by this gene localizes to the endoplasmic reticulum, where it catalyzes the esterification of all-trans-retinol into all-trans-retinyl ester. This reaction is an important step in vitamin A metabolism in the visual system. Mutations in this gene have been associated with early-onset severe retinal dystrophy and Leber congenital amaurosis 14. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 37 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 4-154744366-G-T is Pathogenic according to our data. Variant chr4-154744366-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 667379.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRAT | NM_004744.5 | c.40G>T | p.Glu14Ter | stop_gained | 2/3 | ENST00000336356.4 | |
LRAT | NM_001301645.2 | c.40G>T | p.Glu14Ter | stop_gained | 2/3 | ||
LRAT | XM_047416405.1 | c.40G>T | p.Glu14Ter | stop_gained | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRAT | ENST00000336356.4 | c.40G>T | p.Glu14Ter | stop_gained | 2/3 | 1 | NM_004744.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727236
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Leber congenital amaurosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 27, 2018 | The p.Glu14X variant in LRAT has not been previously reported in individuals wit h Leber congenital amaurosis and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 14, which is predicted to lead to a truncated or absent protein. Loss of function of the LRA T gene is strongly associated with autosomal recessive Leber congenital amaurosi s. In summary, although additional studies are required to fully establish its c linical significance, this variant meets criteria to be classified as likely pat hogenic for Leber congenital amaurosis in an autosomal recessive manner. ACMG/AM P Criteria applied: PVS1_Strong, PM2. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
0.66
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -40
Find out detailed SpliceAI scores and Pangolin per-transcript scores at