9-95249128-A-G

Position:

• chr9-95249128-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000289081.8(FANCC):​c.164T>C​(p.Met55Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on 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. M55I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCC ENST00000289081.8 missense, splice_region
• Scores: Splicing: ADA: 0.005237
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCC	NM_000136.3	c.164T>C	p.Met55Thr	missense_variant, splice_region_variant	2/15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.164T>C	p.Met55Thr	missense_variant, splice_region_variant	2/15	1	NM_000136.3	ENSP00000289081	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2016

This sequence change replaces methionine with threonine at codon 55 of the FANCC protein (p.Met55Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FANCC-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;T;.;T;.;.;.
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.010
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.68	.;T;T;T;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.2	D;D;.;.;D;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.010	D;D;.;.;D;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;.;D;.;.;.
Polyphen		0.11	B;B;.;.;B;.;.;.
Vest4		0.37
MutPred		0.71		Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);Loss of stability (P = 0.0209);
MVP		0.86
MPC		0.26
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.45
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0052
dbscSNV1_RF	Benign	0.066
SpliceAI score (max)		0.0		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: rs1060502513; hg19: chr9-98011410;