rs1415268424

chr9-95249284-T-Achr9-95249284-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000136.3(FANCC):c.8A>T(p.Gln3Leu) 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 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q3H) 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: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34951487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.8A>T	p.Gln3Leu	missense_variant	2/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.8A>T	p.Gln3Leu	missense_variant	2/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250312 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727204

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: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T;.;T;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.;.;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.1	D;D;.;.;D;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D;.;.;D;.;.;.
Sift4G	Uncertain	0.0050	D;D;D;.;D;.;.;.
Polyphen		0.80	P;P;.;.;D;.;.;.
Vest4		0.17
MutPred		0.59		Loss of disorder (P = 0.0872);Loss of disorder (P = 0.0872);Loss of disorder (P = 0.0872);Loss of disorder (P = 0.0872);Loss of disorder (P = 0.0872);Loss of disorder (P = 0.0872);Loss of disorder (P = 0.0872);Loss of disorder (P = 0.0872);
MVP		0.82
MPC		0.12
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.42
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1415268424; hg19: chr9-98011566;