11-22625426-G-T

Variant names:

• chr11-22625426-G-T
• rs61753271
• NM_022725.4:c.385C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022725.4(FANCF):​c.385C>A​(p.Leu129Ile) 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. 13/22 in silico tools predict 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. L129V) 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: 1.16
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2339654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCF	NM_022725.4	c.385C>A	p.Leu129Ile	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.385C>A	p.Leu129Ile	missense_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3
GAS2	ENST00000528582.5	c.-408G>T		upstream_gene_variant		3		ENSP00000432584.1
GAS2	ENST00000648096.1	n.-83G>T		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249958 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Uncertain:1

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 129 of the FANCF protein (p.Leu129Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FANCF-related conditions. 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 expected to disrupt FANCF protein function with a positive 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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.041
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.068
Sift	Benign	0.45	T
Sift4G	Benign	0.21	T
Vest4		0.26
ClinPred		0.61	D
GERP RS		4.3
PromoterAI		0.075	Neutral
Varity_R		0.21
gMVP		0.076
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs61753271; hg19: chr11-22646972;