rs149126845
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_032444.4(SLX4):āc.1372A>Gā(p.Lys458Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K458R) has been classified as Uncertain significance.
Frequency
Consequence
NM_032444.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLX4 | NM_032444.4 | c.1372A>G | p.Lys458Glu | missense_variant | 7/15 | ENST00000294008.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLX4 | ENST00000294008.4 | c.1372A>G | p.Lys458Glu | missense_variant | 7/15 | 5 | NM_032444.4 | P1 | |
SLX4 | ENST00000466154.5 | n.2593A>G | non_coding_transcript_exon_variant | 5/7 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000828 AC: 126AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000798 AC: 199AN: 249516Hom.: 0 AF XY: 0.000879 AC XY: 119AN XY: 135436
GnomAD4 exome AF: 0.000775 AC: 1133AN: 1461608Hom.: 0 Cov.: 32 AF XY: 0.000789 AC XY: 574AN XY: 727120
GnomAD4 genome ? AF: 0.000827 AC: 126AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60AN XY: 74470
ClinVar
Submissions by phenotype
Fanconi anemia complementation group P Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 19, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2022 | Observed in an individual with seizures and developmental delay who was de novo for a variant in the SLC1A2 gene as well as compound heterozygous for the K458E variant and another SLX4 missense variant; however follow up testing for Fanconi anemia was normal (Guella et al., 2017); Identified in individuals with breast, ovarian, or head/neck cancers, but also observed in controls (Shah et al., 2013; Bakker et al. 2013; Chandrasekharappa et al., 2017; Rizzolo et al., 2019; Song et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23840564, 32546565, 28678401, 22911665, 30613976, 28777935) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2017 | - - |
not specified Uncertain:1Benign:1
Likely benign, no assertion criteria provided | curation | Leiden Open Variation Database | Aug 31, 2012 | Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 13, 2020 | DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.1372A>G, in exon 7 that results in an amino acid change, p.Lys458Glu. This sequence change has been previously described in a patient with breast cancer, however there is not enough evidence to support the pathogenicity of this sequence change in these studies (PMID: 22911665 and PMID: 23840564). This sequence change has been described in the gnomAD database with a low population frequency of 0.075% (dbSNP rs149126845). The p.Lys458Glu change affects a highly conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys458Glu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys458Glu change remains unknown at this time. - |
Fanconi anemia Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at