rs45451294

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P320S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 32)

Exomes 𝑓: 0.016 ( 241 hom. )

Consequence

FANCF
NM_022725.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.912

Publications

23 publications found

Variant links:

COSMIC-nc: COSV59416879

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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 134351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022725.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCF	NM_022725.4	MANE Select	c.959C>T	p.Pro320Leu	missense	Exon 1 of 1	NP_073562.1	A3KME0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCF	ENST00000327470.6	TSL:6 MANE Select	c.959C>T	p.Pro320Leu	missense	Exon 1 of 1	ENSP00000330875.3	Q9NPI8

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1740

AN:

152124

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0126

AC:

3175

AN:

251492

AF XY:

0.0130

show subpopulations

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 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.:

AF XY:

0.0161

AC XY:

11708

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00305

AC:

102

AN:

33480

American (AMR)

AF:

0.0115

AC:

514

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0276

AC:

722

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0111

AC:

955

AN:

86258

European-Finnish (FIN)

AF:

0.00475

AC:

254

AN:

53420

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0180

AC:

20024

AN:

1111992

Other (OTH)

AF:

0.0158

AC:

957

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1474

2948

4421

5895

7369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

728

1456

2184

2912

3640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0114

AC:

1738

AN:

152242

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

759

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00334

AC:

139

AN:

41556

American (AMR)

AF:

0.00981

AC:

150

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00851

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00396

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0181

AC:

1234

AN:

68006

Other (OTH)

AF:

0.0151

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

176

265

353

441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0163

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0181

AC:

156

ExAC

AF:

0.0126

AC:

1535

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0189

EpiControl

AF:

0.0196

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Fanconi anemia complementation group F (3)

not specified (4)

Fanconi anemia (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0072

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

0.91

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.096

Sift

Benign

0.92

Sift4G

Benign

0.77

Polyphen

0.90

Vest4

0.074

MPC

0.83

ClinPred

0.028

GERP RS

4.6

Varity_R

0.086

gMVP

0.19

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over