rs45451294

chr11-22624852-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022725.4(FANCF):c.959C>T(p.Pro320Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,614,116 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 32)
  • Exomes 𝑓: 0.016 (241 hom.)
• Consequence: FANCF NM_022725.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.912

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072051883).
• BP6: Variant 11-22624852-G-A is Benign according to our data. Variant chr11-22624852-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22624852-G-A is described in Lovd as [Benign]. Variant chr11-22624852-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1738/152242) while in subpopulation NFE AF= 0.0181 (1234/68006). AF 95% confidence interval is 0.0173. There are 14 homozygotes in gnomad4. There are 759 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCF	NM_022725.4	c.959C>T	p.Pro320Leu	missense_variant	1/1	ENST00000327470.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCF	ENST00000327470.6	c.959C>T	p.Pro320Leu	missense_variant	1/1		NM_022725.4	P1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1740 AN: 152124 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0126 AC: 3175 AN: 251492 Hom.: 33 AF XY: 0.0130 AC XY: 1766 AN XY: 135920

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0108

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0162 AC: 23613 AN: 1461874 Hom.: 241 Cov.: 32 AF XY: 0.0161 AC XY: 11708 AN XY: 727242

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0111

Gnomad4 FIN exome AF: 0.00475

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0114 AC: 1738 AN: 152242 Hom.: 14 Cov.: 32 AF XY: 0.0102 AC XY: 759 AN XY: 74430

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00851

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0172 Hom.: 34

Bravo AF: 0.0117

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0181 AC: 156

ExAC AF: 0.0126 AC: 1535

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	This variant is associated with the following publications: (PMID: 28202063) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	FANCF: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Fanconi anemia complementation group F Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 01, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.096
Sift	Benign	0.92	T
Sift4G	Benign	0.77	T
Polyphen		0.90	P
Vest4		0.074
MPC		0.83
ClinPred		0.028	T
GERP RS		4.6
Varity_R		0.086
gMVP		0.19

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

Other links and lift over

dbSNP: rs45451294; hg19: chr11-22646398; COSMIC: COSV59416879; COSMIC: COSV59416879;