rs116380142
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1
The NM_001113378.2(FANCI):c.3660T>C(p.Ser1220=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,611,274 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
FANCI
NM_001113378.2 synonymous
NM_001113378.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.07
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 Benign. Variant got -8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
?
Variant 15-89312912-T-C is Benign according to our data. Variant chr15-89312912-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414872.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=3}.
BP7
?
Synonymous conserved (PhyloP=1.07 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00117 (176/149916) while in subpopulation AFR AF= 0.00415 (169/40734). AF 95% confidence interval is 0.00364. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCI | NM_001113378.2 | c.3660T>C | p.Ser1220= | synonymous_variant | 35/38 | ENST00000310775.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCI | ENST00000310775.12 | c.3660T>C | p.Ser1220= | synonymous_variant | 35/38 | 1 | NM_001113378.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00117 AC: 176AN: 149842Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000286 AC: 72AN: 251398Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135884
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GnomAD4 exome AF: 0.000112 AC: 164AN: 1461358Hom.: 1 Cov.: 31 AF XY: 0.0000935 AC XY: 68AN XY: 727046
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Fanconi anemia Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 17, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Fanconi anemia complementation group I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 04, 2019 | - - |
FANCI-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 20, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
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Dann
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RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at