rs36045913

Positions:

chr11-22624986-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_022725.4(FANCF):c.825G>A(p.Leu275=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,614,146 control chromosomes in the GnomAD database, including 512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 49 hom., cov: 33)

Exomes 𝑓: 0.022 ( 463 hom. )

Consequence

FANCF
NM_022725.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 0.197

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]

FANCF links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 11-22624986-C-T is Benign according to our data. Variant chr11-22624986-C-T is described in ClinVar as [Benign]. Clinvar id is 241444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22624986-C-T is described in Lovd as [Benign]. Variant chr11-22624986-C-T is described in Lovd as [Pathogenic]. Variant chr11-22624986-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.197 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2738/152262) while in subpopulation NFE AF= 0.028 (1903/68018). AF 95% confidence interval is 0.0269. There are 49 homozygotes in gnomad4. There are 1385 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCF	NM_022725.4 linkuse as main transcript	c.825G>A	p.Leu275=	synonymous_variant	1/1	ENST00000327470.6	NP_073562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCF	ENST00000327470.6 linkuse as main transcript	c.825G>A	p.Leu275=	synonymous_variant	1/1		NM_022725.4	ENSP00000330875	P1

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2739

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.0405

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0280

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0183

AC:

4595

AN:

251448

Hom.:

AF XY:

0.0184

AC XY:

2507

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00879

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00346

Gnomad FIN exome

AF:

0.0432

Gnomad NFE exome

AF:

0.0255

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0225

AC:

32834

AN:

1461884

Hom.:

463

Cov.:

AF XY:

0.0222

AC XY:

16158

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00245

Gnomad4 AMR exome

AF:

0.00899

Gnomad4 ASJ exome

AF:

0.0183

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00410

Gnomad4 FIN exome

AF:

0.0423

Gnomad4 NFE exome

AF:

0.0253

Gnomad4 OTH exome

AF:

0.0180

GnomAD4 genome

AF:

0.0180

AC:

2738

AN:

152262

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1385

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00325

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.0405

Gnomad4 NFE

AF:

0.0280

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0233

Hom.:

Bravo

AF:

0.0147

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0247

EpiControl

AF:

0.0207

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	FANCF: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2020	This variant is associated with the following publications: (PMID: 27884173, 17924555) -

Fanconi anemia complementation group F

Pathogenic:1Benign: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. -
Pathogenic, flagged submission	curation	Leiden Open Variation Database	Feb 07, 2011	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan de Winter. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Fanconi anemia

Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.4

DANN

Benign

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over