chr6-35452547-T-C
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The NM_021922.3(FANCE):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000428 in 1,168,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000043 ( 0 hom. )
Consequence
FANCE
NM_021922.3 start_lost
NM_021922.3 start_lost
Scores
3
2
11
Clinical Significance
Conservation
PhyloP100: 0.157
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 Pathogenic. Variant got 13 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_021922.3 (FANCE) was described as [Likely_pathogenic] in ClinVar as 1696377
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-35452547-T-C is Pathogenic according to our data. Variant chr6-35452547-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1060674.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCE | NM_021922.3 | c.2T>C | p.Met1? | start_lost | 1/10 | ENST00000229769.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCE | ENST00000229769.3 | c.2T>C | p.Met1? | start_lost | 1/10 | 1 | NM_021922.3 | P1 | |
FANCE | ENST00000696264.1 | c.2T>C | p.Met1? | start_lost | 1/8 | ||||
FANCE | ENST00000648059.1 | c.2T>C | p.Met1? | start_lost, NMD_transcript_variant | 1/11 | ||||
FANCE | ENST00000696265.1 | c.2T>C | p.Met1? | start_lost, NMD_transcript_variant | 1/9 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000428 AC: 5AN: 1168868Hom.: 0 Cov.: 30 AF XY: 0.00000882 AC XY: 5AN XY: 567020
GnomAD4 exome
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5
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1168868
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30
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5
AN XY:
567020
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Fanconi anemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 04, 2023 | Variant summary: FANCE c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. One of two in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 53280 control chromosomes. Alternatively, N-terminal truncation or extension of the encoded protein can also occur due to translation initiation at an alternative initiation codon. The next downstream in-frame initiation codon is at Met 99. Activation of the potential downstream translation initiation site would result in a shortened protein missing the first 98 amino acids from the protein sequence. Other pathogenic variants have been reported upstream of this alternate codon (e.g. p.Gln31Ter, p.Arg89Ter; ClinVar and HGMD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Fanconi Anemia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Fanconi anemia complementation group E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change affects the initiator methionine of the FANCE mRNA. The next in-frame methionine is located at codon 99. This variant is present in population databases (no rsID available, gnomAD 0.007%). Disruption of the initiator codon has been observed in individual(s) with clinical features of FANCE-related conditions (PMID: 33084842). ClinVar contains an entry for this variant (Variation ID: 1060674). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Gain of glycosylation at M1 (P = 8e-04);
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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