rs1554828492

Variant names:

• chr9-95107269-C-A
• rs1554828492
• NM_000136.3:c.1330G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-95107269-C-A
• chr9-95107269-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000136.3(FANCC):​c.1330G>T​(p.Val444Phe) 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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. V444I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FANCC NM_000136.3 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• 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]

LOC107987102 (HGNC:):

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-95107268-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2445319.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.1330G>T	p.Val444Phe	missense_variant, splice_region_variant	Exon 14 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.1330G>T	p.Val444Phe	missense_variant, splice_region_variant	Exon 14 of 15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V444F variant (also known as c.1330G>T) is located in coding exon 13 of the FANCC gene. The valine at codon 444 is replaced by phenylalanine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 13. This amino acid position is conserved. 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	0.16
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		1.6
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.95	P;P
Vest4		0.60
MutPred		0.76		Loss of MoRF binding (P = 0.0893);Loss of MoRF binding (P = 0.0893);
MVP		0.87
MPC		0.32
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.28
gMVP		0.46
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1554828492; hg19: chr9-97869551;