rs45553340

Variant names:

• chr11-22622807-A-G
• rs45553340
• NM_022725.4:c.*1879T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.550
• Publications: 1 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]

FANCF Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. 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 rank	MANE	Protein	UniProt
FANCF	NM_022725.4	c.*1879T>C		3_prime_UTR_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.*1879T>C		3_prime_UTR_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 836 AN: 152212 Hom.: 2 Cov.: 32

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

African (AFR) AF: 0.00 AC: 0 AN: 1576

American (AMR) AF: 0.000967 AC: 1 AN: 1034

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 3 AN: 2448

East Asian (EAS) AF: 0.00 AC: 0 AN: 6620

South Asian (SAS) AF: 0.00 AC: 0 AN: 324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.00600 AC: 138 AN: 22986

Other (OTH) AF: 0.00342 AC: 11 AN: 3214

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152330 Hom.: 2 Cov.: 32 AF XY: 0.00542 AC XY: 404 AN XY: 74490

African (AFR) AF: 0.00142 AC: 59 AN: 41590

American (AMR) AF: 0.00353 AC: 54 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00863 AC: 587 AN: 68000

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

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

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group F Uncertain: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.8
DANN	Benign	0.92
PhyloP100		0.55
Mutation Taster		=100/0	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: rs45553340; hg19: chr11-22644353;