rs199592185
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_032444.4(SLX4):c.5040G>T(p.Arg1680Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1680K) has been classified as Uncertain significance.
Frequency
Consequence
NM_032444.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLX4 | NM_032444.4 | c.5040G>T | p.Arg1680Ser | missense_variant | 14/15 | ENST00000294008.4 | |
SLX4 | XM_024450471.2 | c.5040G>T | p.Arg1680Ser | missense_variant | 14/15 | ||
SLX4 | XM_011522715.4 | c.5037G>T | p.Arg1679Ser | missense_variant | 14/15 | ||
SLX4 | XM_047434801.1 | c.4038G>T | p.Arg1346Ser | missense_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLX4 | ENST00000294008.4 | c.5040G>T | p.Arg1680Ser | missense_variant | 14/15 | 5 | NM_032444.4 | P1 | |
ENST00000573982.1 | n.273C>A | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251490Hom.: 0 AF XY: 0.000154 AC XY: 21AN XY: 135922
GnomAD4 exome AF: 0.0000698 AC: 102AN: 1461892Hom.: 1 Cov.: 33 AF XY: 0.000107 AC XY: 78AN XY: 727248
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152278Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74454
ClinVar
Submissions by phenotype
Fanconi anemia complementation group P Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 25, 2020 | A heterozygous missense variant was identified, NM_032444.2(SLX4):c.5040G>T in exon 14 of 15 of the SLX4 gene. This substitution is predicted to create a major amino acid change from arginine to serine at position 1680 of the protein, NP_115820.2(SLX4):p.(Arg1680Ser). The arginine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain. In silico software predicts this variant to be benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.01% (28 heterozygotes, 0 homozygotes). An alternative nucleotide change resulting in the same protein alteration to serine has been reported in the gnomAD database at a frequency of 0.004% (12 heterozygotes, 0 homozygotes). In addition, an alternative residue change at the same location has been reported in the gnomAD database at a frequency of 0.0008%. The alternative nucleotide change resulting in a serine has been previously reported as a VUS (ClinVar), and this variant has been reported in the germline of a patient with head and neck squamous cell carcinoma (Chandrasekharappa, S. et al. (2017)). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 25, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Fanconi anemia Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 16, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at