rs755283850

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000136.3(FANCC):​c.521G>C​(p.Arg174Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R174Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FANCC
NM_000136.3 missense, splice_region

Scores

1
12
6
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FANCCNM_000136.3 linkuse as main transcriptc.521G>C p.Arg174Pro missense_variant, splice_region_variant 6/15 ENST00000289081.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCCENST00000289081.8 linkuse as main transcriptc.521G>C p.Arg174Pro missense_variant, splice_region_variant 6/151 NM_000136.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;T;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.77
.;T;T
M_CAP
Benign
0.050
D
MetaRNN
Pathogenic
0.93
D;D;D
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.1
M;M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-3.4
D;D;.
REVEL
Uncertain
0.41
Sift
Uncertain
0.0070
D;D;.
Sift4G
Uncertain
0.022
D;D;D
Polyphen
0.99
D;D;.
Vest4
0.86
MutPred
0.78
Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP
0.89
MPC
0.39
ClinPred
0.98
D
GERP RS
3.1
Varity_R
0.68
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.91
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.91
Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-97933361; API