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rs587778326

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000136.3(FANCC):c.1585A>T(p.Thr529Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T529N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

FANCC
NM_000136.3 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69
Variant links:
Genes affected
FANCC (HGNC:3584): (FA complementation group C) 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 C. [provided by RefSeq, Jul 2008]
AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a mutagenesis_site No effect on protective function from mitomycin C-genotoxicity. (size 0) in uniprot entity FANCC_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28846014).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FANCCNM_000136.3 linkuse as main transcriptc.1585A>T p.Thr529Ser missense_variant 15/15 ENST00000289081.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCCENST00000289081.8 linkuse as main transcriptc.1585A>T p.Thr529Ser missense_variant 15/151 NM_000136.3 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 18, 2019The p.T529S variant (also known as c.1585A>T), located in coding exon 14 of the FANCC gene, results from an A to T substitution at nucleotide position 1585. The threonine at codon 529 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
Cadd
Uncertain
23
Dann
Uncertain
0.99
DEOGEN2
Benign
0.35
T;T
Eigen
Benign
0.12
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.87
D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.29
T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.2
M;M
MutationTaster
Benign
0.86
N;N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-2.0
N;N
REVEL
Benign
0.12
Sift
Benign
0.041
D;D
Sift4G
Benign
0.068
T;T
Polyphen
0.59
P;P
Vest4
0.16
MutPred
0.75
Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);
MVP
0.75
MPC
0.21
ClinPred
0.91
D
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.10
gMVP
0.20

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: rs587778326; hg19: chr9-97864081; API