rs141828876
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_000136.3(FANCC):c.705C>T(p.Pro235=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,613,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00086 ( 1 hom. )
Consequence
FANCC
NM_000136.3 synonymous
NM_000136.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.561
Genes affected
FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]
AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
?
Variant 9-95135484-G-A is Benign according to our data. Variant chr9-95135484-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137276.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=1, Uncertain_significance=1}. Variant chr9-95135484-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-0.561 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.705C>T | p.Pro235= | synonymous_variant | 8/15 | ENST00000289081.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.705C>T | p.Pro235= | synonymous_variant | 8/15 | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000427 AC: 65AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000315 AC: 79AN: 251178Hom.: 0 AF XY: 0.000309 AC XY: 42AN XY: 135806
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GnomAD4 exome AF: 0.000856 AC: 1251AN: 1461634Hom.: 1 Cov.: 31 AF XY: 0.000772 AC XY: 561AN XY: 727098
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GnomAD4 genome ? AF: 0.000427 AC: 65AN: 152290Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:3
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | FANCC: BP4, BP7 - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 28, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 18, 2020 | - - |
Fanconi anemia complementation group C Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 02, 2019 | - - |
Fanconi anemia Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 14, 2021 | - - |
FANCC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 20, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The FANCC p.Pro235= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs141828876) as With other allele, ClinVar (classified as benign by GeneDx; classified as likely benign by Invitae, Ambry Genetics), and LOVD 3.0 (likely benign). The variant was identified in control databases in 88 of 277010 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 5 of 24014 chromosomes (freq: 0.0002), Other in 2 of 6468 chromosomes (freq: 0.0003), Latino in 3 of 34402 chromosomes (freq: 0.0001), European Non-Finnish in 78 of 126580 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Pro235= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2017 | 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
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Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at