2-58161561-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018062.4(FANCL):c.981T>C(p.Ser327Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,608,860 control chromosomes in the GnomAD database, including 321,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.69 ( 37646 hom., cov: 32)

Exomes 𝑓: 0.62 ( 283716 hom. )

Consequence

FANCL
NM_018062.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.551

Publications

38 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 2-58161561-A-G is Benign according to our data. Variant chr2-58161561-A-G is described in ClinVar as Benign. ClinVar VariationId is 257495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.551 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4 link	c.981T>C	p.Ser327Ser	synonymous_variant	Exon 12 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.981T>C	p.Ser327Ser	synonymous_variant	Exon 12 of 14	1	NM_018062.4	ENSP00000233741.5

Frequencies

GnomAD3 genomes

AF:

0.692

AC:

104904

AN:

151584

Hom.:

37585

Cov.:

show subpopulations

Gnomad AFR

AF:

0.898

Gnomad AMI

AF:

0.498

Gnomad AMR

AF:

0.645

Gnomad ASJ

AF:

0.541

Gnomad EAS

AF:

0.575

Gnomad SAS

AF:

0.672

Gnomad FIN

AF:

0.637

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.608

Gnomad OTH

AF:

0.652

GnomAD2 exomes

AF:

0.643

AC:

161260

AN:

250620

AF XY:

0.638

show subpopulations

Gnomad AFR exome

AF:

0.909

Gnomad AMR exome

AF:

0.680

Gnomad ASJ exome

AF:

0.552

Gnomad EAS exome

AF:

0.558

Gnomad FIN exome

AF:

0.657

Gnomad NFE exome

AF:

0.609

Gnomad OTH exome

AF:

0.623

GnomAD4 exome

AF:

0.621

AC:

905009

AN:

1457158

Hom.:

283716

Cov.:

AF XY:

0.621

AC XY:

450648

AN XY:

725104

show subpopulations

African (AFR)

AF:

0.916

AC:

30556

AN:

33376

American (AMR)

AF:

0.673

AC:

30057

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.547

AC:

14236

AN:

26034

East Asian (EAS)

AF:

0.571

AC:

22595

AN:

39556

South Asian (SAS)

AF:

0.663

AC:

57151

AN:

86152

European-Finnish (FIN)

AF:

0.653

AC:

34863

AN:

53388

Middle Eastern (MID)

AF:

0.557

AC:

3207

AN:

5758

European-Non Finnish (NFE)

AF:

0.608

AC:

674117

AN:

1108018

Other (OTH)

AF:

0.635

AC:

38227

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

15666

31332

46998

62664

78330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18292

36584

54876

73168

91460

<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:

0.692

AC:

105025

AN:

151702

Hom.:

37646

Cov.:

AF XY:

0.693

AC XY:

51339

AN XY:

74130

show subpopulations

African (AFR)

AF:

0.898

AC:

37237

AN:

41476

American (AMR)

AF:

0.645

AC:

9808

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.541

AC:

1874

AN:

3462

East Asian (EAS)

AF:

0.575

AC:

2967

AN:

5160

South Asian (SAS)

AF:

0.670

AC:

3227

AN:

4818

European-Finnish (FIN)

AF:

0.637

AC:

6718

AN:

10540

Middle Eastern (MID)

AF:

0.609

AC:

179

AN:

294

European-Non Finnish (NFE)

AF:

0.608

AC:

41183

AN:

67734

Other (OTH)

AF:

0.656

AC:

1378

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1526

3052

4578

6104

7630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.631

Hom.:

139602

Bravo

AF:

0.700

Asia WGS

AF:

0.681

AC:

2364

AN:

3476

EpiCase

AF:

0.609

EpiControl

AF:

0.597

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group L

Benign:5

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: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

not provided

Benign:2

Jan 14, 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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.61

CADD

Benign

3.2

(source)

DANN

Benign

0.74

PhyloP100

-0.55

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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