11-22625809-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_022725.4(FANCF):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000479 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

FANCF
NM_022725.4 start_lost

Scores

8
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 5.45
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 145 codons. Genomic position: 22625378. Lost 0.385 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-22625809-A-G is Pathogenic according to our data. Variant chr11-22625809-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 304209.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCFNM_022725.4 linkc.2T>C p.Met1? start_lost Exon 1 of 1 ENST00000327470.6 NP_073562.1 Q9NPI8A3KME0
GAS2XM_011519972.4 linkc.-2605A>G upstream_gene_variant XP_011518274.1
GAS2XM_047426745.1 linkc.-8636A>G upstream_gene_variant XP_047282701.1
GAS2XM_047426746.1 linkc.-2605A>G upstream_gene_variant XP_047282702.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCFENST00000327470.6 linkc.2T>C p.Met1? start_lost Exon 1 of 1 6 NM_022725.4 ENSP00000330875.3 Q9NPI8
GAS2ENST00000528582 linkc.-25A>G 5_prime_UTR_variant Exon 1 of 6 3 ENSP00000432584.1 E9PQ74
GAS2ENST00000648096.1 linkn.301A>G non_coding_transcript_exon_variant Exon 1 of 1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461748
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Fanconi anemia complementation group F Pathogenic:1Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Apr 08, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fanconi anemia Pathogenic:1
Jul 18, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant disrupts the N-terminal domain of the FANCF protein, which stabilizes the interaction with FANCA and FANCG, and is also essential for the binding of the FANCC/FANCE subcomplex (PMID: 15262960). While functional studies have not been performed to directly test the effect of this variant on FANCF protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 304209). Disruption of the initiator codon has been observed in individuals with Fanconi anemia (PMID: 27714961; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the FANCF mRNA. The next in-frame methionine is located at codon 145. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.58
D
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Benign
-0.50
T
PROVEAN
Pathogenic
-5.0
D
REVEL
Uncertain
0.48
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.97
MutPred
0.99
Gain of phosphorylation at M1 (P = 0.0649);
MVP
0.81
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.95
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs745495865; hg19: chr11-22647355; API