rs104886456
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000136.3(FANCC):c.456+4A>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000172 in 1,556,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000136.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCC | NM_000136.3 | c.456+4A>T | splice_region_variant, intron_variant | Intron 5 of 14 | ENST00000289081.8 | NP_000127.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000210 AC: 32AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000287 AC: 72AN: 250510Hom.: 0 AF XY: 0.000273 AC XY: 37AN XY: 135552
GnomAD4 exome AF: 0.000167 AC: 235AN: 1404378Hom.: 0 Cov.: 25 AF XY: 0.000175 AC XY: 123AN XY: 702208
GnomAD4 genome 0.000210 AC: 32AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74374
ClinVar
Submissions by phenotype
Fanconi anemia complementation group C Pathogenic:12Other:1
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Variant summary: FANCC c.456+4A>T affects a conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant, and 4/5 Alamut algorithms predict a weaker splice donor site for the variant, which is predicted to increase exon skipping. These in silico predictions are supported by functional studies showing that this variant leads to a truncated protein product. This variant is found in 28/117194 control chromosomes at a frequency of 0.0002389, which does not significantly exceed maximal expected frequency of a pathogenic FANCC allele (0.0017678).The variant has been cited in multiple severe FA patients in homozygous state and in mild FA patients in compound heterozygous state. In addition, multiple clinical diagnostic labs classified this variant as pathogenic. This intronic variant is considered a known common disease variant in the literature, therefore, this is a disease variant and was classified as pathogenic. -
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The c.456+4A>T variant identified in FANCC has previously been reported as homozygous and compound heterozygous in multiple individuals with Fanconi anemia [PMID: 20301575] and determined as a pathogenic founder variant in the Ashkenazi Jewish population [PMID: 7492758]. Multiple independent laboratories have deposited this variant as Pathogenic in the ClinVar database (Variation ID: 12045). The c.456+4A>T variant is observed in 137 alleles (0.023% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), and this frequency is low enough to be consistent with a recessive carrier frequency. The c.456+4A>T variant is located in the splice region after exon 5 of this 15-exon gene and is predicted to affect mRNA splicing (Splice AI = 0.895). Functional studies demonstrated aberrant splicing and reduced DNA end-joining activity in patient-derived fibroblast cells carrying the c.456+4A>T variant [PMID: 8348157, 15364573]. Based on available evidence this inherited c.456+4A>T variant identified in FANCC is classified as Pathogenic. -
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The FANCC c.456+4A>T variant is a common pathogenic FANCC variant, particularly in the Ashkenazi Jewish population (Verlander et al. 1995; Auerbach, 2009). Across a selection of available literature, the c.456+4A>T variant has been identified in a homozygous state in 12 probands, in a heterozygous state in one proband in whom a second variant was not identified, and in a heterozygous state in seven unaffected family members (Whitney et al. 1993; Futaki et al. 2000; Auerbach, 2009). The c.456+4A>T variant was absent from 25 controls and is reported at a frequency of 0.006016 in the European (non-Finnish) population of the Genome Aggregation Database. Verlander et al. (1995) determined that the carrier frequency of the c.456+4A>T variant in the Ashkenazi Jewish population is approximately one in 89, or 1.1%. RT-PCR analysis indicated the c.456+4A>T variant disrupts splicing and results in the production of two abnormal products, an 111bp in-frame deletion and a 40bp partial removal of exon 4 (Whitney et al. 1993). Patient-derived fibroblasts demonstrated that the c.456+4A>T variant significantly reduced DNA end-joining activity compared with wild type cells (Donahue et al. 2004). Based on the evidence, the c.456+4A>T variant is classified as pathogenic for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto. -
Common in Ashkenazi Jewish; also reported in a Japanese cohort -
NM_000136.2(FANCC):c.456+4A>T is classified as pathogenic in the context of Fanconi anemia. Sources cited for classification include the following: 8081385, 7492758, 8348157, 11427142, 9207444, and 10666230. Classification of NM_000136.2(FANCC):c.456+4A>T is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
not provided Pathogenic:4
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In the published literature, the variant has been reported in individuals with Fanconi anemia type C (FA-C) (PMIDs: 31558676 (2020), 28425259 (2017), 23613520 (2013), 10666230 (2000), 9207444 (1997), 8639804 (1996), 7492758 (1995), 8128956 (1994)) and in individuals with various cancer types, including rhabdomyosarcoma (PMID: 34308366 (2021)), hereditary breast and/or ovarian cancer (PMIDs: 32885271 (2021), 32235514 (2020), 30322717 (2018), 26681312 (2015)), anaplastic astrocytoma (PMID: 32570879 (2020)), testicular cancer (PMID: 30676620 (2019)), melanoma (PMID: 26681312 (2015)) and pancreatic cancer (PMID: 26681312 (2015)). Functional studies have demonstrated this variant leads to exon skipping (PMID: 8348157 (1993)) and decreased DNA end joining ability (PMID: 15364573 (2004)). Additionally, this variant is a well-known founder variant in the Ashkenazi Jewish population (PMIDs: 10666230 (2000), 7492758 (1995), 8348157 (1993)). 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, this variant is classified as pathogenic. -
Canonical splice site variant demonstrated to result in an in-frame loss of exon 5 (Whitney 1993), which includes portions of the critical RED, FAZF, GRP94, and Hsp70 binding regions (Gordon 2000); Published functional studies demonstrate a damaging effect: decreased nuclear localization, p53 phosphorylation and binding to co-factors in response to drug-induced DNA damage (Loke 2015); Also known as IVS4+4A>T; This variant is associated with the following publications: (PMID: 22701786, 10666230, 26681312, 20301575, 30792206, 31513304, 8348157, 23613520, 26778106, 27619566, 26976241, 28301456, 28717661, 28495237, 27832981, 28425259, 28627524, 30683899, 30322717, 30676620, 20869034, 25236480, 7492758, 25545896, 30249500, 32570879, 30945166, 31558676, 25652403, 32235514, 8734810, 32885271, 34308366, 34426522, Gordon2000[Book]) -
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Fanconi anemia Pathogenic:3
NG_011707.1(NM_000136.2):c.456+4A>T is also known as IVS4+4A>T in literatures. It has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Whitney et al reported that this variant resulted exon skipping due to abnormal gene splicing (PMID: 8348157). FANCC c.456+4A>T has been published in both the compound heterozygous and homozygous state in individuals with Fanconi Anemia (PMID: 8348157). It is also determined as a pathogenic founder variant in the Ashkenazi Jewish population(PMID: 7492758). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PM3_Strong; PP4. -
This sequence change falls in intron 5 of the FANCC gene. It does not directly change the encoded amino acid sequence of the FANCC protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs104886456, gnomAD 0.6%). This variant has been observed in individuals with Fanconi anemia (PMID: 8081385, 8348157, 10666230). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS4+4A>T. ClinVar contains an entry for this variant (Variation ID: 12045). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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FANCC-related disorder Pathogenic:1
The FANCC c.456+4A>T variant is predicted to interfere with splicing. This well-documented splicing variant in the FANCC gene is one of the more common variants known to cause Fanconi anemia and is present at a particularly high frequency among the Ashkenazi Jewish population (For example see: Whitney et al. 1993. PubMed ID: 8348157; Merrill et al. 2005. PubMed ID: 15662710; Chandrasekharappa et al. 2013. PubMed ID: 23613520). This variant is reported in 0.62% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12045/). This variant is interpreted as pathogenic. -
Malignant tumor of breast Pathogenic:1
The FANCC c.456+4A>T variant was identified in 19 of 116 proband chromosomes (frequency: 0.16) from individuals or families with Fanconi Anemia (Whitney 1993, Futaki 2000). The variant was also identified in dbSNP (ID: rs104886456) as “With Pathogenic allele”, ClinVar and Clinvitae (8x classified as pathogenic by GeneDx, EGL Genetic Diagnostics, Invitae, Children's Mercy Hospital, Ambry Genetics, Counsyl, OMIM, Gene Reviews), and LOVD 3.0 (83 entries). The variant was not identified in the COSMIC or MutDB databases. The variant was identified in control databases in 73 of 276626 chromosomes at a frequency of 0.0003, increasing the likelihood this could be a low frequency variant in certain populations of origin (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 2 of 6450 chromosomes (freq: 0.0003), Latino in 1 of 34376 chromosomes (freq: 0.00003), European Non-Finnish in 9 of 126366 chromosomes (freq: 0.00007), and Ashkenazi Jewish in 61 of 10140 chromosomes (freq: 0.006), while the variant was not observed in the African, East Asian, European Finnish, or South Asian populations. In a study of carrier status of the American Ashkenazi Jewish population, 35 of 6208 chromosomes (freq. 0.006) were positive for this variant, which was not found in any of 1126 control chromosomes from the Iraqi Sephardic Jewish population. This variant is described as a founder mutation in the Ashkenazi Jewish population with a severe phenotype in Ashkenazi Jewish Fanconi Anemia (FA) patients, but a milder phenotype in Japanese FA patients, suggesting the presence of unidentified modifying factors (de Vries 2012, Futaki 2000). The pathogenic effect of this variant in FA is well described in the literature; however its role in cancer risk is less clear. An Israeli study of asymptomatic heterozygous carriers of this variant failed to demonstrate an increased risk of cancer; however the number of patients studied was relatively small and the average age was low at 31 years old (Laitman 2015). The c.456+4A>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 3 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. This variant has been shown to result in the skipping of exon 5 (Whitney 1993). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.456+4A>T intronic pathogenic mutation results from an A to T substitution 4 nucleotides after coding exon 4 in the FANCC gene. This well-described mutation has been reported in multiple homozygous and compound heterozygous individuals with Fanconi anemia, and it is the most common mutation in FANCC in individuals of Ashkenazi Jewish descent (Whitney MA et al. Nat. Genet. 1993 Jun;4:202-5; Whitney MA et al. Hum. Mutat., 1994;3:339-41; Verlander PC et al. Am. J. Hum. Genet. 1994 Apr;54:595-601; Yamashita T et al. Blood. 1996 May;87:4424-32; Futaki M et al. Blood. 2000 Feb;95:1493-8; Kutler DI et al. Fam. Cancer. 2004;3:241-8; Chandrasekharappa SC et al. Blood. 2013 May;121:e138-4; Aftab I et al. Turk J Med Sci, 2017 Apr;47:391-398). This alteration was also identified in 7/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in aberrant mRNA splicing (Whitney MA et al. Nat. Genet. 1993 Jun;4:202-5; Chandrasekharappa SC et al. Blood. 2013 May;121:e138-4). Of note, this mutation is also designated as IVS4+4A>T and c.711+4A>T in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at