NM_000136.3:c.1312_1329+68dupCAGAGAGCACAGACTATGGTGGGTAGCAGGCCCCACTGCATGTGTTTGGGGTGGGCTCTGGGGGGCTGAGAGGAGCTTGCAGAGAG

Variant names:

• chr9-95111394-C-CCTCTCTGCAAGCTCCTCTCAGCCCCCCAGAGCCCACCCCAAACACATGCAGTGGGGCCTGCTACCCACCATAGTCTGTGCTCTCTG
• rs1554829415
• NM_000136.3:c.1312_1329+68dupCAGAGAGCACAGACTATGGTGGGTAGCAGGCCCCACTGCATGTGTTTGGGGTGGGCTCTGGGGGGCTGAGAGGAGCTTGCAGAGAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_000136.3(FANCC):​c.1312_1329+68dupCAGAGAGCACAGACTATGGTGGGTAGCAGGCCCCACTGCATGTGTTTGGGGTGGGCTCTGGGGGGCTGAGAGGAGCTTGCAGAGAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FANCC NM_000136.3 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0670
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP5: Variant 9-95111394-C-CCTCTCTGCAAGCTCCTCTCAGCCCCCCAGAGCCCACCCCAAACACATGCAGTGGGGCCTGCTACCCACCATAGTCTGTGCTCTCTG is Pathogenic according to our data. Variant chr9-95111394-C-CCTCTCTGCAAGCTCCTCTCAGCCCCCCAGAGCCCACCCCAAACACATGCAGTGGGGCCTGCTACCCACCATAGTCTGTGCTCTCTG is described in ClinVar as Pathogenic. ClinVar VariationId is 456154.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.1312_1329+68dupCAGAGAGCACAGACTATGGTGGGTAGCAGGCCCCACTGCATGTGTTTGGGGTGGGCTCTGGGGGGCTGAGAGGAGCTTGCAGAGAG		intron_variant	Intron 13 of 14	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.1329+68_1329+69insCAGAGAGCACAGACTATGGTGGGTAGCAGGCCCCACTGCATGTGTTTGGGGTGGGCTCTGGGGGGCTGAGAGGAGCTTGCAGAGAG		intron_variant	Intron 13 of 14	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Pathogenic:1

Jul 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln437Hisfs*39) in the FANCC gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FANCC-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 24773018). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.067
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554829415; hg19: chr9-97873676;