rs140326236
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1
The NM_182548.4(LHFPL5):c.411G>A(p.Ala137=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A137A) has been classified as Uncertain significance.
Frequency
Consequence
NM_182548.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LHFPL5 | NM_182548.4 | c.411G>A | p.Ala137= | splice_region_variant, synonymous_variant | 1/4 | ENST00000360215.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LHFPL5 | ENST00000360215.3 | c.411G>A | p.Ala137= | splice_region_variant, synonymous_variant | 1/4 | 1 | NM_182548.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000985 AC: 15AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000173 AC: 43AN: 248990Hom.: 0 AF XY: 0.000178 AC XY: 24AN XY: 135046
GnomAD4 exome AF: 0.000211 AC: 308AN: 1461374Hom.: 0 Cov.: 31 AF XY: 0.000209 AC XY: 152AN XY: 727002
GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 227500). This variant has not been reported in the literature in individuals affected with LHFPL5-related conditions. This variant is present in population databases (rs140326236, gnomAD 0.03%). This sequence change affects codon 137 of the LHFPL5 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LHFPL5 protein. It affects a nucleotide within the consensus splice site. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2015 | p.Ala137Ala in exon 1 of LHFPL5: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and has been identif ied in 14/63960 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140326236). This variant is located in t he last three bases of the exon, which is part of the 5? splice region. However, computational tools do not suggest an impact to splicing, this nucleotide posit ion is not highly conserved through species and a G>A change at this position do es not diverge from the splice consensus sequence and is therefore unlikely to i mpact splicing. - |
LHFPL5-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 14, 2019 | This variant is classified as likely 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