NM_001018113.3:c.2098T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001018113.3(FANCB):​c.2098T>C​(p.Phe700Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,479 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F700F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

FANCB
NM_001018113.3 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.27

Publications

0 publications found
Variant links:
Genes affected
FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]
FANCB Gene-Disease associations (from GenCC):
  • Fanconi anemia complementation group B
    Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
  • VACTERL association, X-linked, with or without hydrocephalus
    Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • VACTERL with hydrocephalus
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07616672).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCBNM_001018113.3 linkc.2098T>C p.Phe700Leu missense_variant Exon 9 of 10 ENST00000650831.1 NP_001018123.1 Q8NB91A0A024RBW1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCBENST00000650831.1 linkc.2098T>C p.Phe700Leu missense_variant Exon 9 of 10 NM_001018113.3 ENSP00000498215.1 Q8NB91

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD2 exomes
AF:
0.00000546
AC:
1
AN:
183306
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000122
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
9.12e-7
AC:
1
AN:
1096479
Hom.:
0
Cov.:
30
AF XY:
0.00000276
AC XY:
1
AN XY:
361909
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26362
American (AMR)
AF:
0.00
AC:
0
AN:
35203
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19363
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30191
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54096
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40532
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4133
European-Non Finnish (NFE)
AF:
0.00000119
AC:
1
AN:
840570
Other (OTH)
AF:
0.00
AC:
0
AN:
46029
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Fanconi anemia Uncertain:1
Sep 01, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 700 of the FANCB protein (p.Phe700Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant has not been reported in the literature in individuals with FANCB-related disease. ClinVar contains an entry for this variant (Variation ID: 456181). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

not provided Uncertain:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The FANCB p.Phe700Leu variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs1232355920) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 1 of 183306 chromosomes (1 hemizygous) at a frequency of 0.000005455 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 1 of 81804 chromosomes (freq: 0.000012), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Phe700 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
13
DANN
Benign
0.42
DEOGEN2
Benign
0.057
T;T;T
FATHMM_MKL
Benign
0.49
N
LIST_S2
Benign
0.54
T;.;T
M_CAP
Benign
0.0021
T
MetaRNN
Benign
0.076
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.60
N;N;.
PhyloP100
1.3
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.69
N;N;N
REVEL
Benign
0.017
Sift
Benign
1.0
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0010
B;B;.
Vest4
0.21
MutPred
0.23
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
0.30
MPC
0.12
ClinPred
0.035
T
GERP RS
2.5
Varity_R
0.11
Mutation Taster
=98/2
polymorphism

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

Other links and lift over

dbSNP: rs1232355920; hg19: chrX-14862692; API