rs950623649

chr9-95171109-T-Achr9-95171109-T-Cchr9-95171109-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000136.3(FANCC):c.491A>T(p.Asn164Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. N164T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.491A>T	p.Asn164Ile	missense_variant	6/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.491A>T	p.Asn164Ile	missense_variant	6/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461334 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 164 of the FANCC protein (p.Asn164Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 526314). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCC protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 26, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2022

The p.N164I variant (also known as c.491A>T), located in coding exon 5 of the FANCC gene, results from an A to T substitution at nucleotide position 491. The asparagine at codon 164 is replaced by isoleucine, an amino acid with dissimilar properties. 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	0.27
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.42	T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	0.82	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.024	D;D;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.77
MutPred		0.62		Loss of disorder (P = 0.0087);Loss of disorder (P = 0.0087);Loss of disorder (P = 0.0087);
MVP		0.85
MPC		0.36
ClinPred		0.98	D
GERP RS		2.6
Varity_R		0.30
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs950623649; hg19: chr9-97933391;