chr16-3591053-C-T
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_032444.4(SLX4):c.2585G>A(p.Arg862Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,614,058 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R862R) has been classified as Likely benign.
Frequency
Consequence
NM_032444.4 missense
Scores
Clinical Significance
Conservation
Publications
- Fanconi anemia complementation group PInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152232Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000597 AC: 15AN: 251400 AF XY: 0.0000442 show subpopulations
GnomAD4 exome AF: 0.0000670 AC: 98AN: 1461826Hom.: 0 Cov.: 36 AF XY: 0.0000743 AC XY: 54AN XY: 727218 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000276 AC: 42AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22AN XY: 74376 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Fanconi anemia complementation group P Uncertain:4
This variant has not been reported in the literature in association with disease. This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.09% [38/41460]; https://gnomad.broadinstitute.org/variant/16-3591053-C-T?dataset=gnomad_r3), and is present in ClinVar, with multiple laboratories classifying it as of uncertain significance (Variation ID:319165). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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not specified Uncertain:1
Variant summary: SLX4 c.2585G>A (p.Arg862Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251400 control chromosomes. This frequency does not allow for any conclusion about variant significance. c.2585G>A has been reported in the literature in at least one individual meeting criteria for hereditary breast and ovarian cancer, where it was classified as a VUS by the authors (e.g. Oliver_2019). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31921681). ClinVar contains an entry for this variant (Variation ID: 319165). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Fanconi anemia Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 862 of the SLX4 protein (p.Arg862Gln). This variant is present in population databases (rs143558209, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with SLX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 319165). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
SLX4-related disorder Uncertain:1
The SLX4 c.2585G>A variant is predicted to result in the amino acid substitution p.Arg862Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3641054-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at