NM_000136.3:c.1555dupA
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000136.3(FANCC):c.1555dupA(p.Thr519AsnfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000136.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.1555dupA | p.Thr519AsnfsTer9 | frameshift_variant | Exon 15 of 15 | ENST00000289081.8 | NP_000127.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461690Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727136
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74372
ClinVar
Submissions by phenotype
Fanconi anemia complementation group C Pathogenic:2
Variant summary: FANCC c.1555dupA (p.Thr519AsnfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg548X). The variant was absent in 251020 control chromosomes (gnomAD). c.1555dupA (also described in the literature as 1806insA) has been reported in compound heterozygosity with another pathogenic variant in one individual (Lo Ten Foe_1996). This individual was reported with normal complete blood cell count and observed phenotypic reversion to MMC resistance which was determined to be due to a detected mitotic crossover event between the mutated sites deduced to have occurred in the patient's hematopoietic system which lead to the production of a wild-type allele and an allele having the two mutations in cis (Lo Ten Foe_1997). Nevertheless, Lo Ten Foe et al (1996) using a functional assay demonstrated that the specific variant was not capable of restoring MMC hypersensitivity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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Fanconi anemia Pathogenic:1
This sequence change creates a premature translational stop signal (p.Thr519Asnfs*9) in the FANCC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the FANCC protein. This variant is present in population databases (rs794726667, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 8829660). This variant is also known as 1806insA. ClinVar contains an entry for this variant (Variation ID: 12048). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FANCC function (PMID: 8882868). This variant disrupts a region of the FANCC protein in which other variant(s) (p.Arg548*) have been determined to be pathogenic (PMID: 8103176, 8882868, 24584348). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Identified with a pathogenic FANCC variant, phase (cis or trans) unknown, in a patient with Fanconi anemia (PMID: 8829660); Frameshift variant predicted to result in abnormal protein length as the last 40 amino acids are replaced with 8 different amino acids, and other similar variants have been reported in HGMD; Published functional studies demonstrate an inability to correct MMC hypersensitivity suggesting loss of function (PMID: 8882868); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1806insA; This variant is associated with the following publications: (PMID: 8882868, 8829660) -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.1555dupA variant, located in coding exon 14 of the FANCC gene, results from a duplication of A at nucleotide position 1555, causing a translational frameshift with a predicted alternate stop codon (p.T519Nfs*9). This alteration occurs at the 3' terminus of FANCC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 7% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at