GeneBe

rs774170058

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000136.3(FANCC):​c.455delA​(p.Asn152IlefsTer6) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000000698 in 1,433,398 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

FANCC
NM_000136.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.61

Publications

0 publications found
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]
FANCC Gene-Disease associations (from GenCC):
  • Fanconi anemia complementation group C
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • colorectal cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • malignant pancreatic neoplasm
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • ovarian cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • prostate cancer
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • breast cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCCNM_000136.3 linkc.455delA p.Asn152IlefsTer6 frameshift_variant, splice_region_variant Exon 5 of 15 ENST00000289081.8 NP_000127.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCCENST00000289081.8 linkc.455delA p.Asn152IlefsTer6 frameshift_variant, splice_region_variant Exon 5 of 15 1 NM_000136.3 ENSP00000289081.3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.98e-7
AC:
1
AN:
1433398
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
715040
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32722
American (AMR)
AF:
0.00
AC:
0
AN:
44682
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25940
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39450
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85640
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53396
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5712
European-Non Finnish (NFE)
AF:
9.20e-7
AC:
1
AN:
1086516
Other (OTH)
AF:
0.00
AC:
0
AN:
59340
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs774170058; hg19: chr9-97934319; COSMIC: COSV56663169; COSMIC: COSV56663169; API