rs761291501
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_018062.4(FANCL):āc.2T>Gā(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 0.000000684 in 1,461,740 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 Pathogenic (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
FANCL
NM_018062.4 start_lost
NM_018062.4 start_lost
Scores
3
3
10
Clinical Significance
Conservation
PhyloP100: 1.14
Genes affected
FANCL (HGNC:20748): (FA complementation group L) This gene encodes a ubiquitin ligase that is a member of the Fanconi anemia complementation group (FANC). Members of this group are related by their assembly into a common nuclear protein complex rather than by sequence similarity. This gene encodes the protein for complementation group L that mediates monoubiquitination of FANCD2 as well as FANCI. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2018]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_018062.4 (FANCL) was described as [Likely_pathogenic] in ClinVar as 1335392
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-58241312-A-C is Pathogenic according to our data. Variant chr2-58241312-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 862463.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCL | NM_018062.4 | c.2T>G | p.Met1? | start_lost | 1/14 | ENST00000233741.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCL | ENST00000233741.9 | c.2T>G | p.Met1? | start_lost | 1/14 | 1 | NM_018062.4 | P4 | |
ENST00000608934.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461740Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727164
GnomAD4 exome
AF:
AC:
1
AN:
1461740
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727164
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Fanconi anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | This sequence change affects the initiator methionine of the FANCL mRNA. The next in-frame methionine is located at codon 74. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with clinical features of FANCL-related conditions (PMID: 33727708; Invitae). ClinVar contains an entry for this variant (Variation ID: 862463). This variant disrupts the E2-like fold (ELF) domain of the FANCL protein, which is required for its interaction with the FANCB-FAAP100 complex as well as for non-covalent binding to ubiquitin (PMID: 26149689, 27986371). While functional studies have not been performed to directly test the effect of this variant on FANCL protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PROVEAN
Benign
N;N;N;N;N
REVEL
Benign
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;.;.
Polyphen
B;B;B;B;.
Vest4
MutPred
Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at