chr6-35458422-A-C
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_021922.3(FANCE):āc.1095A>Cā(p.Arg365Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: š 0.00053 ( 0 hom., cov: 32)
Exomes š: 0.000064 ( 0 hom. )
Consequence
FANCE
NM_021922.3 missense
NM_021922.3 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 3.26
Genes affected
FANCE (HGNC:3586): (FA complementation group E) 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 E. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03198865).
BP6
Variant 6-35458422-A-C is Benign according to our data. Variant chr6-35458422-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134338.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCE | NM_021922.3 | c.1095A>C | p.Arg365Ser | missense_variant | 5/10 | ENST00000229769.3 | NP_068741.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FANCE | ENST00000229769.3 | c.1095A>C | p.Arg365Ser | missense_variant | 5/10 | 1 | NM_021922.3 | ENSP00000229769 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000526 AC: 80AN: 152136Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000155 AC: 39AN: 251488Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135920
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GnomAD4 exome AF: 0.0000636 AC: 93AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.0000481 AC XY: 35AN XY: 727236
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GnomAD4 genome AF: 0.000525 AC: 80AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36AN XY: 74436
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Fanconi anemia complementation group E Uncertain:1Benign: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. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
not specified Uncertain:1Other:1
Uncertain significance, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 01, 2022 | DNA sequence analysis of the FANCE gene demonstrated a sequence change, c.1095A>C, in exon 5 that results in an amino acid change, p.Arg365Ser. This sequence change does not appear to have been previously described in individuals with FANCE-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.23% in the African American/African subpopulation (dbSNP rs141268133). The p.Arg365Ser change affects a poorly conserved amino acid residue located in a domain of the FANCE protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg365Ser substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg365Ser change remains unknown at this time. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 0.0823);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at