rs144908351

Variant names:

Variant summary

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

The NM_001113378.2(FANCI):c.1573A>G(p.Met525Val) variant causes a missense change. The variant allele was found at a frequency of 0.00367 in 1,613,740 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 18 hom. )

Consequence

FANCI
NM_001113378.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 6.81

Publications

18 publications found

Variant links:

Genes affected

FANCI (HGNC:25568): (FA complementation group I) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group I. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FANCI Gene-Disease associations (from GenCC):

Fanconi anemia complementation group I
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCI 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=0.011244476).

BP6

Variant 15-89281825-A-G is Benign according to our data. Variant chr15-89281825-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238309.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00269 (409/152282) while in subpopulation NFE AF = 0.00404 (275/68024). AF 95% confidence interval is 0.00365. There are 5 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCI	NM_001113378.2 link	c.1573A>G	p.Met525Val	missense_variant	Exon 16 of 38	ENST00000310775.12	NP_001106849.1	Q9NVI1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCI	ENST00000310775.12 link	c.1573A>G	p.Met525Val	missense_variant	Exon 16 of 38	1	NM_001113378.2	ENSP00000310842.8		Q9NVI1-3

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

409

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00404

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00230

AC:

577

AN:

251280

AF XY:

0.00215

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00407

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00377

AC:

5512

AN:

1461458

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

2684

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33478

American (AMR)

AF:

0.000626

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.000429

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00466

AC:

5181

AN:

1111792

Other (OTH)

AF:

0.00202

AC:

122

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

256

513

769

1026

1282

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:

0.00269

AC:

409

AN:

152282

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41558

American (AMR)

AF:

0.000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00404

AC:

275

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

122

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:

0.00320

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00213

AC:

259

EpiCase

AF:

0.00333

EpiControl

AF:

0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jul 14, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

â€¢ Observed in cohorts of individuals with a personal and/or family history of cancer; however, several of these individuals also harbored variants in other cancer-related genes and the variant was also observed in control individuals (Cabanillas et al., 2017; Chandrasekharappa et al., 2017; Girard et al., 2019) â€¢ Observed with another FANCI variant of uncertain significance in internal GeneDx whole exome sequencing data in association with aplastic anemia and tongue cancer â€¢ In silico analysis supports that this missense variant does not alter protein structure/function â€¢ Observed in apparent homozygous state in multiple unrelated individuals in large population cohorts (Lek et al., 2016) and in a healthy adult individual tested at GeneDx â€¢ We interpret M525V as a likely benign variant -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FANCI: BP4, BS2 -

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

- -

Fanconi anemia complementation group I

Uncertain:1Benign:2

Jun 07, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in association with hematological disease. This variant is present in the Genome Aggregation Databse (Highest MAF: 0.4% [275/68032], 5 homozygotes https://gnomad.broadinstitute.org/variant/15-89281825-A-G?dataset=gnomad_r3). This variant is also present in ClinVar (Variation ID: 238309). Evoluationary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Nov 18, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Fanconi anemia

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Benign:1

Jan 08, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FANCI-related disorder

Benign:1

Feb 16, 2022

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

.;T

Eigen

Benign

0.10

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

6.8

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.49

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.50

P;B

Vest4

0.65

MVP

0.66

MPC

0.021

ClinPred

0.056

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.63

Mutation Taster

=93/7

polymorphism

(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