rs761291501

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Moderate

The NM_018062.4(FANCL):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FANCL
NM_018062.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.14

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:

ENSG00000273063 (HGNC:):

ENSG00000273063 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 74 codons. Genomic position: 58226781. Lost 0.195 part of the original CDS.

PS1

Another start lost variant in NM_018062.4 (FANCL) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-58241312-A-C is Pathogenic according to our data. Variant chr2-58241312-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 862463.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4 link	c.2T>G	p.Met1?	start_lost	Exon 1 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.2T>G	p.Met1?	start_lost	Exon 1 of 14	1	NM_018062.4	ENSP00000233741.5		Q9NW38-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fanconi anemia

Pathogenic:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the FANCL mRNA. The next in-frame methionine is located at codon 74. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with clinical features of FANCL-related conditions (PMID: 33727708; Invitae). ClinVar contains an entry for this variant (Variation ID: 862463). This variant disrupts the E2-like fold (ELF) domain of the FANCL protein, which is required for its interaction with the FANCB-FAAP100 complex as well as for non-covalent binding to ubiquitin (PMID: 26149689, 27986371). While functional studies have not been performed to directly test the effect of this variant on FANCL protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.026

T;T;.;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.0030

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Benign

-0.92

PROVEAN

Benign

-1.3

N;N;N;N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;.;.

Polyphen

0.17

B;B;B;B;.

Vest4

0.62

MutPred

1.0

Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);

MVP

0.57

ClinPred

0.99

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.68

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