rs55849827

Variant names:

• chr2-58232097-G-A
• rs55849827
• NM_018062.4:c.112C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 14/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.55
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 221092.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00305 (465/152222) while in subpopulation NFE AF = 0.00407 (277/67980). AF 95% confidence interval is 0.00368. There are 2 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018062.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	NM_018062.4	MANE Select	c.112C>T	p.Leu38Phe	missense	Exon 2 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.112C>T	p.Leu38Phe	missense	Exon 2 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.112C>T	p.Leu38Phe	missense	Exon 2 of 15	NP_001397721.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	ENST00000233741.9	TSL:1 MANE Select	c.112C>T	p.Leu38Phe	missense	Exon 2 of 14	ENSP00000233741.5
	FANCL	ENST00000403295.8	TSL:1	c.112C>T	p.Leu38Phe	missense	Exon 2 of 13	ENSP00000386097.3
	FANCL	ENST00000449070.6	TSL:1	c.96+9121C>T		intron	N/A	ENSP00000401280.2

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 465 AN: 152104 Hom.: 2 Cov.: 32

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

GnomAD2 exomes AF: 0.00337 AC: 846 AN: 251092 AF XY: 0.00337

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 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.: 15 Cov.: 30 AF XY: 0.00391 AC XY: 2841 AN XY: 726762

African (AFR) AF: 0.000448 AC: 15 AN: 33446

American (AMR) AF: 0.000693 AC: 31 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00847 AC: 221 AN: 26106

East Asian (EAS) AF: 0.000530 AC: 21 AN: 39586

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86230

European-Finnish (FIN) AF: 0.00782 AC: 417 AN: 53328

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00441 AC: 4899 AN: 1111310

Other (OTH) AF: 0.00268 AC: 162 AN: 60338

GnomAD4 genome AF: 0.00305 AC: 465 AN: 152222 Hom.: 2 Cov.: 32 AF XY: 0.00332 AC XY: 247 AN XY: 74416

African (AFR) AF: 0.000963 AC: 40 AN: 41558

American (AMR) AF: 0.00170 AC: 26 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00811 AC: 86 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00407 AC: 277 AN: 67980

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00379 Hom.: 2

Bravo AF: 0.00234

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.000289 AC: 1 AN: 3474

EpiCase AF: 0.00305

EpiControl AF: 0.00374

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Jan 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27153395, 24459294)

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 31, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCL: BP4, BS2

Fanconi anemia complementation group L Benign:3

Mar 08, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia Benign:2

Jun 19, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jun 24, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCL-related disorder Benign:1

Oct 14, 2019

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.24
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.037	D
Polyphen		0.98	D
Vest4		0.55
MVP		0.51
MPC		0.040
ClinPred		0.022	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.68
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs55849827; hg19: chr2-58459232; COSMIC: COSV99288072;