NM_000136.3:c.843+1G>A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000136.3(FANCC):c.843+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000093 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000136.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.843+1G>A | splice_donor_variant, intron_variant | Intron 8 of 14 | ENST00000289081.8 | NP_000127.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251408Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461532Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727060
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74336
ClinVar
Submissions by phenotype
Fanconi anemia complementation group C Pathogenic:5
Variant summary: FANCC c.843+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251408 control chromosomes (gnomAD). The variant, c.843+1G>A, has been reported in heterozygous state in individuals affected with breast cancer (e.g. Yi_2019, Lerner-Ellis_2021), but it was also found in healthy controls (Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
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Fanconi anemia Pathogenic:1
This sequence change affects a donor splice site in intron 8 of the FANCC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs587779909, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 30630526, 32885271). ClinVar contains an entry for this variant (Variation ID: 127547). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Malignant tumor of breast Pathogenic:1
The FANCC c.843+1G>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs587779909) as "With Likely pathogenic allele", in ClinVar (classified as likely pathogenic by Invitae and Counsyl), and in LOVD 3.0 (2x). The variant was identified in control databases in 3 of 277168 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34414 chromosomes (freq: 0.00003), European in 2 of 126684 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The c.843+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing relative to the normal allele. 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 pathogenic role for this variant. This variant is classified as likely pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.843+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the FANCC gene. This alteration was identified as a germline finding in 1/66 Chinese triple negative breast cancer patients who underwent tumor and germline next generation sequencing using a 43-gene panel (Yi D et al. Hum. Genomics, 2019 01;13:4). Another study detected this alteration in 0/3030 pancreatic cancer cases and 2/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that a different alteration impacting the same splice donor site, c.843+5G>A, results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at