rs1554829415

chr9-95111394-C-CCTCTCTGCAAGCTCCTCTCAGCCCCCCAGAGCCCACCCCAAACACATGCAGTGGGGCCTGCTACCCACCATAGTCTGTGCTCTCTG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000136.3(FANCC):c.1329+68_1329+69insCAGAGAGCACAGACTATGGTGGGTAGCAGGCCCCACTGCATGTGTTTGGGGTGGGCTCTGGGGGGCTGAGAGGAGCTTGCAGAGAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95111394-C-CCTCTCTGCAAGCTCCTCTCAGCCCCCCAGAGCCCACCCCAAACACATGCAGTGGGGCCTGCTACCCACCATAGTCTGTGCTCTCTG is Pathogenic according to our data. Variant chr9-95111394-C-CCTCTCTGCAAGCTCCTCTCAGCCCCCCAGAGCCCACCCCAAACACATGCAGTGGGGCCTGCTACCCACCATAGTCTGTGCTCTCTG is described in ClinVar as [Pathogenic]. Clinvar id is 456154.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.1329+68_1329+69insCAGAGAGCACAGACTATGGTGGGTAGCAGGCCCCACTGCATGTGTTTGGGGTGGGCTCTGGGGGGCTGAGAGGAGCTTGCAGAGAG		intron_variant		ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.1329+68_1329+69insCAGAGAGCACAGACTATGGTGGGTAGCAGGCCCCACTGCATGTGTTTGGGGTGGGCTCTGGGGGGCTGAGAGGAGCTTGCAGAGAG		intron_variant		1	NM_000136.3	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 28, 2017

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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554829415; hg19: chr9-97873676;