2-58221997-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018062.4(FANCL):​c.319C>G​(p.Pro107Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

FANCL
NM_018062.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61
Variant links:
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24786341).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCLNM_018062.4 linkc.319C>G p.Pro107Ala missense_variant Exon 5 of 14 ENST00000233741.9 NP_060532.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCLENST00000233741.9 linkc.319C>G p.Pro107Ala missense_variant Exon 5 of 14 1 NM_018062.4 ENSP00000233741.5 Q9NW38-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Fanconi anemia Uncertain:1
Aug 26, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline with alanine at codon 107 of the FANCL protein (p.Pro107Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FANCL-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
17
DANN
Benign
0.88
DEOGEN2
Benign
0.024
T;T;.;T;T
Eigen
Benign
0.076
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.77
T;T;T;T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.25
T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.6
.;L;L;.;.
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-2.5
N;N;N;N;.
REVEL
Benign
0.060
Sift
Benign
0.090
T;T;T;T;.
Sift4G
Benign
0.26
T;T;T;.;T
Polyphen
0.0060
B;B;B;B;.
Vest4
0.45
MutPred
0.54
Loss of glycosylation at P107 (P = 0.003);Loss of glycosylation at P107 (P = 0.003);Loss of glycosylation at P107 (P = 0.003);.;.;
MVP
0.45
MPC
0.0094
ClinPred
0.66
D
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754028115; hg19: chr2-58449132; API