dbSNP rs55849827: FANCL:p.Leu38Phe (chr2-58232097-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 1.55

Publications

7 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, Laboratory for Molecular Medicine, G2P
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 -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

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	A0A8Q3SIK5

Ensembl Transcripts

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	Q9NW38-1
FANCL	ENST00000403295.8	TSL:1	c.112C>T	p.Leu38Phe	missense	Exon 2 of 13	ENSP00000386097.3	B5MC31
FANCL	ENST00000449070.6	TSL:1	c.96+9121C>T		intron	N/A	ENSP00000401280.2	C9JZA9

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

GnomAD2 exomes

AF:

0.00337

AC:

846

AN:

251092

AF XY:

0.00337

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 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

African (AFR)

AF:

0.000448

AC:

AN:

33446

American (AMR)

AF:

0.000693

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00847

AC:

221

AN:

26106

East Asian (EAS)

AF:

0.000530

AC:

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:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00441

AC:

4899

AN:

1111310

Other (OTH)

AF:

0.00268

AC:

162

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

277

553

830

1106

1383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.00305

AC:

465

AN:

152222

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41558

American (AMR)

AF:

0.00170

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5186

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00811

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00407

AC:

277

AN:

67980

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00379

Hom.:

Bravo

AF:

0.00234

Asia WGS

AF:

0.000289

AC:

AN:

3474

EpiCase

AF:

0.00305

EpiControl

AF:

0.00374

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Fanconi anemia complementation group L (3)

Fanconi anemia (2)

FANCL-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.017

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.7

PhyloP100

1.6

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

REVEL

Benign

0.24

Sift

Uncertain

0.011

Sift4G

Uncertain

0.037

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.68

Mutation Taster

=98/2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over