rs755283850

Positions:

• chr9-95171079-C-G
• chr9-95171079-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000136.3(FANCC):​c.521G>C​(p.Arg174Pro) 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. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R174Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCC NM_000136.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.521G>C	p.Arg174Pro	missense_variant, splice_region_variant	6/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.521G>C	p.Arg174Pro	missense_variant, splice_region_variant	6/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.86
MutPred		0.78		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.89
MPC		0.39
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.68
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-97933361;