rs758597713
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001113378.2(FANCI):βc.3493delβ(p.Asp1165ThrfsTer34) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000204 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000066 ( 0 hom., cov: 32)
Exomes π: 0.000016 ( 0 hom. )
Consequence
FANCI
NM_001113378.2 frameshift
NM_001113378.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.59
Genes affected
FANCI (HGNC:25568): (FA complementation group I) 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 I. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-89306148-AG-A is Pathogenic according to our data. Variant chr15-89306148-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 408200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89306148-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCI | NM_001113378.2 | c.3493del | p.Asp1165ThrfsTer34 | frameshift_variant | 32/38 | ENST00000310775.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCI | ENST00000310775.12 | c.3493del | p.Asp1165ThrfsTer34 | frameshift_variant | 32/38 | 1 | NM_001113378.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251486Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135920
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727246
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74346
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia Pathogenic:3
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 23, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 08, 2022 | Variant summary: FANCI c.3493delG (p.Asp1165ThrfsX34) 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 associated with Fanconi Anemia in HGMD. The variant allele was found at a frequency of 5.2e-05 in 251486 control chromosomes. c.3493delG has been reported in the literature as a compound heterozygous genotype in individuals affected with Fanconi Anemia (Chandrasekharappa_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2) and likely pathogenic (n=1) . Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change creates a premature translational stop signal (p.Asp1165Thrfs*34) in the FANCI gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCI are known to be pathogenic (PMID: 17452773, 17460694). This variant is present in population databases (rs758597713, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with head and neck squamous cell carcinoma (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 408200). For these reasons, this variant has been classified as Pathogenic. - |
Fanconi anemia complementation group I Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 23, 2021 | - - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Oct 04, 2013 | Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 11, 2021 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at