rs181285048

Variant names:

• chr11-22623202-C-T
• rs181285048
• NM_022725.4:c.*1484G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022725.4(FANCF):​c.*1484G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00832 in 213,688 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (3 hom.)
• Consequence: FANCF NM_022725.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.109
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-22623202-C-T is Benign according to our data. Variant chr11-22623202-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 877849.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00806 (1227/152276) while in subpopulation NFE AF = 0.013 (887/68014). AF 95% confidence interval is 0.0123. There are 5 homozygotes in GnomAd4. There are 566 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCF	NM_022725.4	c.*1484G>A		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.*1484G>A		3_prime_UTR_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3

Frequencies

GnomAD3 genomes AF: 0.00806 AC: 1227 AN: 152158 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00897 AC: 551 AN: 61412 Hom.: 3 Cov.: 0 AF XY: 0.00907 AC XY: 258 AN XY: 28446

African (AFR) AF: 0.00105 AC: 3 AN: 2848

American (AMR) AF: 0.00385 AC: 7 AN: 1816

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 24 AN: 3948

East Asian (EAS) AF: 0.00 AC: 0 AN: 9054

South Asian (SAS) AF: 0.00 AC: 0 AN: 518

European-Finnish (FIN) AF: 0.0238 AC: 1 AN: 42

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 382

European-Non Finnish (NFE) AF: 0.0125 AC: 471 AN: 37668

Other (OTH) AF: 0.00876 AC: 45 AN: 5136

GnomAD4 genome AF: 0.00806 AC: 1227 AN: 152276 Hom.: 5 Cov.: 33 AF XY: 0.00760 AC XY: 566 AN XY: 74448

African (AFR) AF: 0.00265 AC: 110 AN: 41562

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0130 AC: 887 AN: 68014

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

Alfa AF: 0.0110 Hom.: 1

Bravo AF: 0.00750

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group F Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.93
DANN	Benign	0.23
PhyloP100		-0.11
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: rs181285048; hg19: chr11-22644748;