rs147390386

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021922.3(FANCE):​c.1591T>A​(p.Leu531Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,070 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

FANCE
NM_021922.3 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.58
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31739601).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCENM_021922.3 linkc.1591T>A p.Leu531Met missense_variant Exon 10 of 10 ENST00000229769.3 NP_068741.1 Q9HB96

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCEENST00000229769.3 linkc.1591T>A p.Leu531Met missense_variant Exon 10 of 10 1 NM_021922.3 ENSP00000229769.2 Q9HB96

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000507
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000636
AC:
16
AN:
251486
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.000800
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1460858
Hom.:
0
Cov.:
30
AF XY:
0.0000151
AC XY:
11
AN XY:
726804
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.000507
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.000212
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000906
AC:
11

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fanconi anemia complementation group E Uncertain:2
Apr 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 20, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 531 of the FANCE protein (p.Leu531Met). This variant is present in population databases (rs147390386, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with FANCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 471923). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FANCE protein function with a positive predictive value of 80%. 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. -

FANCE-related disorder Uncertain:1
Sep 22, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The FANCE c.1591T>A variant is predicted to result in the amino acid substitution p.Leu531Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.064% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-35434102-T-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
T
Eigen
Benign
0.052
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.32
T
MetaSVM
Benign
-0.69
T
MutationAssessor
Uncertain
2.8
M
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.23
Sift
Uncertain
0.010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.53
MVP
0.63
MPC
0.52
ClinPred
0.24
T
GERP RS
0.72
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.37

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: rs147390386; hg19: chr6-35434102; API