rs748342368
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000136.3(FANCC):c.1534-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000136.3 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.1534-5del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000289081.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.1534-5del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000480 AC: 12AN: 250192Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135348
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461532Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727062
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2022 | See Variant Classification Assertion Criteria. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 24, 2022 | To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00037 (13/35416 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on FANCC mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 10, 2019 | Variant summary: FANCC c.1534-5delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 250192 control chromosomes, predominantly at a frequency of 0.00035 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.00035 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1534-5delT in individuals affected with Fanconi Anemia Group C and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Fanconi anemia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Fanconi anemia complementation group C Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at