11-22625459-C-A

Variant names:

• chr11-22625459-C-A
• rs1060501871
• NM_022725.4:c.352G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022725.4(FANCF):​c.352G>T​(p.Gly118Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. G118S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FANCF NM_022725.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.638
• Publications: 0 publications found

Genes affected

FANCF (HGNC:3587): (FA complementation group F) 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 F. [provided by RefSeq, Jul 2008]

GAS2 (HGNC:4167): (growth arrest specific 2) The protein encoded by this gene is a caspase-3 substrate that plays a role in regulating microfilament and cell shape changes during apoptosis. It can also modulate cell susceptibility to p53-dependent apoptosis by inhibiting calpain activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2017]

GAS2 Gene-Disease associations (from GenCC):

• hearing loss disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hearing loss, autosomal recessive 125

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38585556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCF	NM_022725.4	c.352G>T	p.Gly118Cys	missense_variant	Exon 1 of 1	ENST00000327470.6	NP_073562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCF	ENST00000327470.6	c.352G>T	p.Gly118Cys	missense_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3
GAS2	ENST00000528582.5	c.-375C>A		upstream_gene_variant		3		ENSP00000432584.1
GAS2	ENST00000648096.1	n.-50C>A		upstream_gene_variant

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

Fanconi anemia Uncertain:1

Nov 08, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces glycine with cysteine at codon 118 of the FANCF protein (p.Gly118Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FANCF-related disease. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.64
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.19
Sift	Benign	0.096	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.37		Gain of catalytic residue at P117 (P = 0.0116);
MVP		0.68
MPC		0.89
ClinPred		0.86	D
GERP RS		5.4
PromoterAI		-0.010	Neutral
Varity_R		0.29
gMVP		0.27
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1060501871; hg19: chr11-22647005;