rs55849827

chr2-58232097-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_018062.4(FANCL):c.112C>T(p.Leu38Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,613,042 control chromosomes in the GnomAD database, including 17 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 15 hom. )

Consequence

FANCL
NM_018062.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 1.55

Variant links:

Genes affected

FANCL (HGNC:20748): (FA complementation group L) This gene encodes a ubiquitin ligase that is a member of the Fanconi anemia complementation group (FANC). Members of this group are related by their assembly into a common nuclear protein complex rather than by sequence similarity. This gene encodes the protein for complementation group L that mediates monoubiquitination of FANCD2 as well as FANCI. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2018]

FANCL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063643754).

BP6

Variant 2-58232097-G-A is Benign according to our data. Variant chr2-58232097-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221092.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=4, Uncertain_significance=1}. Variant chr2-58232097-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCL	NM_018062.4 linkuse as main transcript	c.112C>T	p.Leu38Phe	missense_variant	2/14	ENST00000233741.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCL	ENST00000233741.9 linkuse as main transcript	c.112C>T	p.Leu38Phe	missense_variant	2/14	1	NM_018062.4	P4	Q9NW38-1

Frequencies

GnomAD3 genomes

AF:

0.00306

AC:

465

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00811

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00407

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00337

AC:

846

AN:

251092

Hom.:

AF XY:

0.00337

AC XY:

458

AN XY:

135718

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00734

Gnomad EAS exome

AF:

0.00147

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00704

Gnomad NFE exome

AF:

0.00428

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00403

AC:

5893

AN:

1460820

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

2841

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00847

Gnomad4 EAS exome

AF:

0.000530

Gnomad4 SAS exome

AF:

0.00146

Gnomad4 FIN exome

AF:

0.00782

Gnomad4 NFE exome

AF:

0.00441

Gnomad4 OTH exome

AF:

0.00268

GnomAD4 genome

AF:

0.00305

AC:

465

AN:

152222

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00663

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00811

Gnomad4 NFE

AF:

0.00407

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00425

Hom.:

Bravo

AF:

0.00234

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00330

AC:

400

Asia WGS

AF:

0.000289

AC:

AN:

3474

EpiCase

AF:

0.00305

EpiControl

AF:

0.00374

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2020	This variant is associated with the following publications: (PMID: 27153395, 24459294) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FANCL: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Fanconi anemia

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Fanconi anemia complementation group L

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 08, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 24, 2021

- -

FANCL-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.066

T;T;.;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.0064

T;T;T;T

MetaSVM

Benign

-0.47

MutationTaster

Benign

0.75

D;D;D;D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

N;N;N;.

REVEL

Benign

0.24

Sift

Uncertain

0.011

D;D;D;.

Sift4G

Uncertain

0.037

D;D;D;D

Polyphen

0.98

D;D;D;.

Vest4

0.55

MVP

0.51

MPC

0.040

ClinPred

0.022

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.68

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