Genetic Variant FANCL:c.375-49C>G (chr2-58204275-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018062.4(FANCL):c.375-49C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,318,008 control chromosomes in the GnomAD database, including 9,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1944 hom., cov: 32)

Exomes 𝑓: 0.11 ( 7961 hom. )

Consequence

FANCL
NM_018062.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.204

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 2-58204275-G-C is Benign according to our data. Variant chr2-58204275-G-C is described in ClinVar as [Benign]. Clinvar id is 257494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4 link	c.375-49C>G		intron_variant	Intron 5 of 13	ENST00000233741.9	NP_060532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCL	ENST00000233741.9 link	c.375-49C>G		intron_variant	Intron 5 of 13	1	NM_018062.4	ENSP00000233741.5		Q9NW38-1

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

21950

AN:

151898

Hom.:

1933

Cov.:

show subpopulations

Gnomad AFR

AF:

0.249

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.0867

Gnomad ASJ

AF:

0.0645

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.123

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0971

Gnomad OTH

AF:

0.116

GnomAD3 exomes

AF:

0.118

AC:

29533

AN:

249512

Hom.:

2146

AF XY:

0.116

AC XY:

15719

AN XY:

135160

show subpopulations

Gnomad AFR exome

AF:

0.261

Gnomad AMR exome

AF:

0.0769

Gnomad ASJ exome

AF:

0.0658

Gnomad EAS exome

AF:

0.192

Gnomad SAS exome

AF:

0.147

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.0955

Gnomad OTH exome

AF:

0.0990

GnomAD4 exome

AF:

0.110

AC:

128216

AN:

1165992

Hom.:

7961

Cov.:

AF XY:

0.110

AC XY:

65628

AN XY:

594460

show subpopulations

Gnomad4 AFR exome

AF:

0.262

Gnomad4 AMR exome

AF:

0.0812

Gnomad4 ASJ exome

AF:

0.0659

Gnomad4 EAS exome

AF:

0.219

Gnomad4 SAS exome

AF:

0.147

Gnomad4 FIN exome

AF:

0.127

Gnomad4 NFE exome

AF:

0.0984

Gnomad4 OTH exome

AF:

0.110

GnomAD4 genome

AF:

0.145

AC:

21998

AN:

152016

Hom.:

1944

Cov.:

AF XY:

0.146

AC XY:

10834

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.250

Gnomad4 AMR

AF:

0.0871

Gnomad4 ASJ

AF:

0.0645

Gnomad4 EAS

AF:

0.200

Gnomad4 SAS

AF:

0.168

Gnomad4 FIN

AF:

0.123

Gnomad4 NFE

AF:

0.0971

Gnomad4 OTH

AF:

0.119

Alfa

AF:

0.116

Hom.:

250

Bravo

AF:

0.145

Asia WGS

AF:

0.220

AC:

765

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group L

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.30

DANN

Benign

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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