rs555753798
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000136.3(FANCC):c.383A>G(p.Asp128Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,118 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 1 hom. )
Consequence
FANCC
NM_000136.3 missense
NM_000136.3 missense
Scores
1
18
Clinical Significance
Conservation
PhyloP100: 1.56
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061351806).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCC | NM_000136.3 | c.383A>G | p.Asp128Gly | missense_variant | 5/15 | ENST00000289081.8 | NP_000127.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FANCC | ENST00000289081.8 | c.383A>G | p.Asp128Gly | missense_variant | 5/15 | 1 | NM_000136.3 | ENSP00000289081.3 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251168Hom.: 1 AF XY: 0.0000295 AC XY: 4AN XY: 135760
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460798Hom.: 1 Cov.: 29 AF XY: 0.00000826 AC XY: 6AN XY: 726796
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GnomAD4 genome 0.00000657 AC: 1AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The FANCC p.D128G variant was identified in dbSNP (ID: rs555753798) as “with uncertain significance allele”. The variant was also identified in control databases in 5 of 251168 chromosomes (1 homozygous) at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 5 of 30598 chromosomes (freq: 0.000163), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) and other populations. In ClinVar, GeneDx previously classified the variant as a variant of uncertain significance. This variant was identified in 1 out of 50 healthy Central Asian individuals from a study of 681 ethnically diverse, healthy adults undergoing whole genome sequencing for mutations in cancer susceptibility genes (Bodian_2014_PMID: 24728327). However, the participants in this study were younger than 50 years old and thus the unaffected status of this individual may not be significant. The FANCC p.D128G variant was not identified in the Fanconi Anemia Mutation Database (LOVD). FANCC p.Asp128Gly occurs at a position that is not conserved in mammals. Two out of four in silico prediction software programs predict a greater than 10% difference in splicing, i.e. an increase in a 5’ splice site (SpliceSpiteFinder-Like and MaxEntScan). Furthermore, two out of five computational programs (SIFT and BLOSUM) predict a high likelihood of impact on the protein structure. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. References: Bodian, Dale L., et al. "Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing." PloS one 9.4 (2014): e94554. Disease information: Biallelic pathogenic variants in the FANCC gene are associated with Fanconi Anemia. Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy (GeneReviews). Approximately 14% of cases of Fanconi anemia are attributed to mutations in FANCC. Heterozygous carriers of a subset of other FA- related genes (e.g. BRCA2, PALB2) are associated with an increased risk of cancer including breast cancer[Seal et al 2006, Berwick et al 2007, Rahman et al 2007. However, literature on the association of cancer risk for FANCC mutation carriers is mixed. There is some evidence that female carriers of FANCC mutations are at an increased risk for breast cancer and that truncating mutation in FANCC may predispose to early-onset pancreatic cancer (Berwick 2007) (Thompson 2012) ( Couch 2005). However other literature has failed to show an increased risk for cancer in FANCC mutation carriers (Seal 2003) (Laitman 2016). The FANCC gene is part of the FA core complex and plays in a role in the Fanconi Anemia Pathway. Pathogenic mutations in FANCC lead to disruption of the FA pathway, resulting in the lack of proper repair of DNA damage, impacting the process of DNA replication and leading to the buildup of errors in DNA. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2016 | This variant is denoted FANCC c.383A>G at the cDNA level, p.Asp128Gly (D128G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant was identified in 1/50 healthy Central Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. FANCC Asp128Gly was not observed at a significant allele frequency in 1000 Genomes. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Asp128Gly occurs at a position that is not conserved and is located in a region of interaction with Hsp70, GRP94, RED and FAZF (Gordon 2000). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether FANCC Asp128Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Fanconi anemia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 26, 2021 | This sequence change replaces aspartic acid with glycine at codon 128 of the FANCC protein (p.Asp128Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs555753798, ExAC 0.01%). 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: 134303). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 21, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2023 | The p.D128G variant (also known as c.383A>G), located in coding exon 4 of the FANCC gene, results from an A to G substitution at nucleotide position 383. The aspartic acid at codon 128 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
.;T;T;T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;.;N;.
REVEL
Benign
Sift
Benign
T;T;.;.;T;.
Sift4G
Benign
T;T;T;.;D;.
Polyphen
B;B;.;.;B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at