chr11-22622807-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_022725.4(FANCF):​c.*1879T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 190,782 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0055 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0040 ( 0 hom. )

Consequence

FANCF
NM_022725.4 3_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.550
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00549 (836/152330) while in subpopulation NFE AF= 0.00863 (587/68000). AF 95% confidence interval is 0.00805. There are 2 homozygotes in gnomad4. There are 404 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FANCFNM_022725.4 linkuse as main transcriptc.*1879T>C 3_prime_UTR_variant 1/1 ENST00000327470.6 NP_073562.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FANCFENST00000327470.6 linkuse as main transcriptc.*1879T>C 3_prime_UTR_variant 1/1 NM_022725.4 ENSP00000330875 P1

Frequencies

GnomAD3 genomes
AF:
0.00549
AC:
836
AN:
152212
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00142
Gnomad AMI
AF:
0.0154
Gnomad AMR
AF:
0.00353
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.0102
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00863
Gnomad OTH
AF:
0.00478
GnomAD4 exome
AF:
0.00398
AC:
153
AN:
38452
Hom.:
0
Cov.:
0
AF XY:
0.00377
AC XY:
67
AN XY:
17786
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000967
Gnomad4 ASJ exome
AF:
0.00123
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00600
Gnomad4 OTH exome
AF:
0.00342
GnomAD4 genome
AF:
0.00549
AC:
836
AN:
152330
Hom.:
2
Cov.:
32
AF XY:
0.00542
AC XY:
404
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.00142
Gnomad4 AMR
AF:
0.00353
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.0102
Gnomad4 NFE
AF:
0.00863
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00503
Hom.:
0
Bravo
AF:
0.00520
Asia WGS
AF:
0.000289
AC:
1
AN:
3472

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fanconi anemia complementation group F Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 20, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.63
CADD
Benign
6.8
DANN
Benign
0.92

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs45553340; hg19: chr11-22644353; API