NM_000135.4:c.2602-9_2602-8delCT
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000135.4(FANCA):c.2602-9_2602-8delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000135.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.2602-9_2602-8delCT | splice_region_variant, intron_variant | Intron 27 of 42 | ENST00000389301.8 | NP_000126.2 | ||
FANCA | NM_001286167.3 | c.2602-9_2602-8delCT | splice_region_variant, intron_variant | Intron 27 of 42 | NP_001273096.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000434 AC: 66AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000713 AC: 179AN: 251154Hom.: 0 AF XY: 0.000707 AC XY: 96AN XY: 135782
GnomAD4 exome AF: 0.000585 AC: 855AN: 1461596Hom.: 0 AF XY: 0.000589 AC XY: 428AN XY: 727090
GnomAD4 genome AF: 0.000434 AC: 66AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74378
ClinVar
Submissions by phenotype
Fanconi anemia Pathogenic:1Uncertain:2Benign:1
The c.2602-9_2602-8delCT variant in FANCA has been reported in two individuals with Fanconi anemia both of whom were compound heterozygous for the variant and a large deletion of FANCA on the other allele (Kimble 2018 PMID: 29098742). It has also been reported in 2 individuals with early-onset renal cell carcinoma, 1 child with neuroblastoma and a distant family history of cancer, and 2 breast cancer patients (initial diagnosis < 55 yrs for both) (Truong 2021 PMID: 34654685, Fiala 2021 PMID: 34308366, del Valle 2020 PMID: 32235514). It was also identified in 0.07% (45/68038) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and is reported in ClinVar (Variation ID 237041). RT-PCR analysis lymphoblastoid cell lines derived from one of the Fanconi anemia patients suggests that the variant results in aberrant splicing, and thus would be expected to lead to a truncated or absent protein. Loss of function of the FANCA gene is an established disease mechanism for autosomal recessive Fanconi anemia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Fanconi anemia. ACMG/AMP criteria applied: PM3, PS3, PP4. -
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Fanconi anemia complementation group A Pathogenic:2Uncertain:1
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not provided Uncertain:3
Reported in two individuals from related families with Fanconi anemia who also have a multi-exon deletion on the opposite allele (in trans); RNA testing in one family suggests this variant leads to aberrant splicing (PMID: 29098742); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25589003, 34426522, 30426508, 34308366, 32235514, 34654685, 30306255, 29098742) -
The FANCA c.2602-9_2602-8del variant has been reported in the published literature in individuals with breast cancer (PMID: 32235514 (2020), 30306255 (2018), 30426508 (2018)), renal cell carcinoma (PMID: 34654685 (2021)), and Fanconi Anemia (PMID: 29098742 (2018)). This variant has been shown to result in aberrant splicing with skipping of exons 28-30 and exon 29 of the FANCA gene (PMID: 29098742 (2018)). The frequency of this variant in the general population, 0.0021 (10/4830 chromosomes in Estonian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on FANCA mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant. -
FANCA: PM3, PM2:Supporting, PS3:Supporting, BP4 -
not specified Uncertain:2
Variant summary: FANCA c.2602-9_2602-8delCT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, the variant has been shown to cause aberrant splicing in a patient derived cell line carrying the variant (Kimble_2018). The variant allele was found at a frequency of 0.00071 in 251154 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in FANCA causing Fanconi Anemia (0.00071 vs 0.0022), allowing no conclusion about variant significance. c.2602-9_2602-8delCT has been reported in the literature in individuals affected with Fanconi Anemia (Kimble_2018) and also in breast cancer patients (Bonache_2018, DelValle_2020, Schubert_2019). These reports do not provide unequivocal conclusions about the variant significance. This variant and FANCA c.1074_1075del/p.Tyr359fs (CV ID: 237032, classified pathogenic) has been observed in an unaffected adult internally. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), likely pathogenic (n=2) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
DNA sequence analysis of the FANCA gene demonstrated a sequence change in intron 27, c.2602-9_2602-8del. This sequence change has been described in the gnomAD database with a frequency of 0.17% in European populations (dbSNP rs577636020). This sequence change, in addition to a large pathogenic deletion, has been identified in a Fanconi anemia family. RNA analysis of these individuals demonstrated skipping of exons 28-30 in the presence of this sequence change (PMID: 29098742). This sequence change is also predicted to have a deleterious effect on splicing based on in silico splice prediction programs. The functional significance of this sequence change is not known at present. -
FANCA-related disorder Uncertain:1
The FANCA c.2602-9_2602-8delCT variant is predicted to result in an intronic deletion. This variant has been reported in two related individuals with Fanconi anemia (FA) who also harbored a partial deletion of FANCA on the opposite allele (Kimble et al. 2018. PubMed ID: 29098742). This variant has also been reported in several individuals with cancer (Bonache et al. 2018. PubMed ID: 30306255; Schubert et al. 2019. PubMed ID: 30426508; Del Valle et al. 2020. PubMed ID: 32235514; Fiala et al. 2021. PubMed ID: 34308366), although some of these individuals also have pathogenic variants in other genes associated with increased cancer risk (see Truong et al. 2021. PubMed ID: 34654685). In silico splicing prediction programs indicate that this variant weakens the adjacent canonical acceptor site (Alamut Visual Plus v1.6.1; SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), and RNA analysis confirmed the presence of altered splice variants in FA patient cell lines (Kimble et al. 2018. PubMed ID: 29098742). A different study in patients with suspected hereditary cancer disorders stated that normal splicing was observed but did not provide supporting data for review (Del Valle et al. 2020. PubMed ID: 32235514). This variant is reported in 0.17% (42 of 25,108) of alleles in individuals of European (Finnish) descent in gnomAD but only occurs in 0.063% (162 of 257,444) of alleles in non-Finnish populations. Taken together, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at