rs143819820

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_018062.4(FANCL):c.203G>C(p.Arg68Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000508 in 1,609,506 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R68Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 1 hom. )

Consequence

FANCL
NM_018062.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 1.90

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group L
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006917268).

BP6

Variant 2-58229827-C-G is Benign according to our data. Variant chr2-58229827-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456243.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000677 (103/152238) while in subpopulation NFE AF = 0.000956 (65/68002). AF 95% confidence interval is 0.000769. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4 link	c.203G>C	p.Arg68Pro	missense_variant	Exon 3 of 14	ENST00000233741.9	NP_060532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCL	ENST00000233741.9 link	c.203G>C	p.Arg68Pro	missense_variant	Exon 3 of 14	1	NM_018062.4	ENSP00000233741.5		Q9NW38-1

Frequencies

GnomAD3 genomes

AF:

0.000677

AC:

103

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000597

AC:

150

AN:

251158

AF XY:

0.000574

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000793

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000491

AC:

715

AN:

1457268

Hom.:

Cov.:

AF XY:

0.000514

AC XY:

373

AN XY:

725318

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33354

American (AMR)

AF:

0.000403

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00372

AC:

AN:

26078

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39566

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000494

AC:

547

AN:

1108048

Other (OTH)

AF:

0.000631

AC:

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000677

AC:

103

AN:

152238

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41542

American (AMR)

AF:

0.000588

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000956

AC:

AN:

68002

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000804

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000470

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group L

Uncertain:2Benign:1

Sep 06, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia

Uncertain:1Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Uncertain:1

Oct 08, 2019

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FANCL-related disorder

Benign:1

Jan 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0062

T;T;.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.55

T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.0069

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

.;N;N;.

PhyloP100

1.9

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.40

N;N;N;.

REVEL

Benign

0.041

Sift

Benign

0.16

T;T;T;.

Sift4G

Benign

0.24

T;T;T;D

Polyphen

0.0070

B;B;B;.

Vest4

0.32

MVP

0.37

MPC

0.0088

ClinPred

0.0072

GERP RS

3.0

Varity_R

0.19

gMVP

0.62

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over