rs113910234

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022725.4(FANCF):c.557C>T(p.Ala186Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00852 in 1,614,164 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0088 ( 96 hom. )

Consequence

FANCF
NM_022725.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.252

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028169155).

BP6

Variant 11-22625254-G-A is Benign according to our data. Variant chr11-22625254-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22625254-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00625 (952/152374) while in subpopulation SAS AF= 0.0153 (74/4834). AF 95% confidence interval is 0.0125. There are 8 homozygotes in gnomad4. There are 440 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCF	NM_022725.4 link	c.557C>T	p.Ala186Val	missense_variant	Exon 1 of 1	ENST00000327470.6	NP_073562.1	Q9NPI8A3KME0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCF	ENST00000327470.6 link	c.557C>T	p.Ala186Val	missense_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3		Q9NPI8

Frequencies

GnomAD3 genomes

AF:

0.00625

AC:

952

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00970

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00830

AC:

2074

AN:

250008

Hom.:

AF XY:

0.00899

AC XY:

1219

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.00113

Gnomad AMR exome

AF:

0.00495

Gnomad ASJ exome

AF:

0.00339

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0169

Gnomad FIN exome

AF:

0.00514

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0125

GnomAD4 exome

AF:

0.00876

AC:

12804

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00925

AC XY:

6726

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00487

Gnomad4 ASJ exome

AF:

0.00383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0167

Gnomad4 FIN exome

AF:

0.00561

Gnomad4 NFE exome

AF:

0.00906

Gnomad4 OTH exome

AF:

0.00856

GnomAD4 genome

AF:

0.00625

AC:

952

AN:

152374

Hom.:

Cov.:

AF XY:

0.00590

AC XY:

440

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0153

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.00972

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.00963

Hom.:

Bravo

AF:

0.00568

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00837

AC:

ExAC

AF:

0.00899

AC:

1092

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0116

EpiControl

AF:

0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Sep 13, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Fanconi anemia complementation group F

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 31, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fanconi anemia

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian cancer

Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Benign:1

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 27, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1, BS2, BP4_Moderate c.557C>T, located in exon 1 of the FANCF gene, is predicted to result in the substitution of alanine by valine at codon 86, p.(Ala186Val). The variant allele was found in 514/30518 alleles, with a filtering allele frequency of 1.5% at 99% confidence, within the South Asian population in the gnomAD v2.1.1 database (non-cancer data set) (BA1). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.041) suggests that it does not affect the protein function according to Pejaver 2022 thresholds (PMID: 36413997) (BP4_Moderate). To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. This variant has been observed in homozygous state in multiple healthy individuals (BS2). This variant has been reported in the ClinVar database (6x benign, 3x likely benign) and in LOVD (1x benign). Based on currently available information, the variant c.557C>T should be considered a benign variant, according to ACMG/AMP classification guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.2

DANN

Benign

0.95

DEOGEN2

Benign

0.071

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

REVEL

Benign

0.041

Sift

Benign

0.45

Sift4G

Benign

0.19

Polyphen

0.040

Vest4

0.078

MVP

0.16

MPC

0.25

ClinPred

0.0024

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.12

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

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