rs761347179
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000136.3(FANCC):c.436_438del(p.Tyr146del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,606,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y146Y) has been classified as Likely benign.
Frequency
Consequence
NM_000136.3 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.436_438del | p.Tyr146del | inframe_deletion | 5/15 | ENST00000289081.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.436_438del | p.Tyr146del | inframe_deletion | 5/15 | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251018Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135726
GnomAD4 exome AF: 0.00000481 AC: 7AN: 1454254Hom.: 0 AF XY: 0.00000552 AC XY: 4AN XY: 723982
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 01, 2022 | Variant summary: FANCC c.436_438delTAT (p.Tyr146del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-05 in 251018 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCC causing Fanconi Anemia Group C (4e-05 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.436_438delTAT in individuals affected with Fanconi Anemia Group C and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 24, 2019 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2022 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Observed in an individual with gastroesophageal cancer (Schrader et al., 2016); This variant is associated with the following publications: (PMID: 26556299) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 17, 2022 | The frequency of this variant in the general population, 0.000026 (3/113518 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in at least one individual with colorectal cancer (PMID: 33563768 (2022)) and one individual with esophagogastric cancer (PMID: 26556299 (2016)). Based on the available information, we are unable to determine the clinical significance of this variant. - |
Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2023 | This variant, c.436_438del, results in the deletion of 1 amino acid(s) of the FANCC protein (p.Tyr146del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs761347179, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 456163). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Fanconi anemia complementation group C Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at