15-89292997-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001113378.2(FANCI):c.2225G>C(p.Cys742Ser) variant causes a missense change. The variant allele was found at a frequency of 0.369 in 1,613,342 control chromosomes in the GnomAD database, including 114,402 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C742R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.30 ( 8407 hom., cov: 32)

Exomes 𝑓: 0.38 ( 105995 hom. )

Consequence

FANCI
NM_001113378.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.96

Publications

58 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024511814).

BP6

Variant 15-89292997-G-C is Benign according to our data. Variant chr15-89292997-G-C is described in ClinVar as Benign. ClinVar VariationId is 257482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113378.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCI	NM_001113378.2	MANE Select	c.2225G>C	p.Cys742Ser	missense	Exon 22 of 38	NP_001106849.1
FANCI	NM_001376911.1		c.2225G>C	p.Cys742Ser	missense	Exon 22 of 38	NP_001363840.1
FANCI	NM_018193.3		c.2225G>C	p.Cys742Ser	missense	Exon 22 of 37	NP_060663.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCI	ENST00000310775.12	TSL:1 MANE Select	c.2225G>C	p.Cys742Ser	missense	Exon 22 of 38	ENSP00000310842.8
FANCI	ENST00000674831.1		c.2225G>C	p.Cys742Ser	missense	Exon 22 of 39	ENSP00000502474.1
FANCI	ENST00000696719.1		c.2225G>C	p.Cys742Ser	missense	Exon 23 of 39	ENSP00000512832.1

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45914

AN:

152012

Hom.:

8406

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0888

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.317

Gnomad ASJ

AF:

0.370

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.384

Gnomad FIN

AF:

0.469

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.390

Gnomad OTH

AF:

0.310

GnomAD2 exomes

AF:

0.365

AC:

91607

AN:

251090

AF XY:

0.373

show subpopulations

Gnomad AFR exome

AF:

0.0801

Gnomad AMR exome

AF:

0.365

Gnomad ASJ exome

AF:

0.379

Gnomad EAS exome

AF:

0.328

Gnomad FIN exome

AF:

0.462

Gnomad NFE exome

AF:

0.385

Gnomad OTH exome

AF:

0.368

GnomAD4 exome

AF:

0.376

AC:

549860

AN:

1461212

Hom.:

105995

Cov.:

AF XY:

0.378

AC XY:

274832

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.0740

AC:

2478

AN:

33474

American (AMR)

AF:

0.359

AC:

16049

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.383

AC:

10002

AN:

26124

East Asian (EAS)

AF:

0.313

AC:

12395

AN:

39664

South Asian (SAS)

AF:

0.392

AC:

33849

AN:

86242

European-Finnish (FIN)

AF:

0.455

AC:

24308

AN:

53396

Middle Eastern (MID)

AF:

0.330

AC:

1899

AN:

5756

European-Non Finnish (NFE)

AF:

0.384

AC:

426805

AN:

1111470

Other (OTH)

AF:

0.366

AC:

22075

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

18227

36454

54682

72909

91136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13202

26404

39606

52808

66010

<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:

0.302

AC:

45912

AN:

152130

Hom.:

8407

Cov.:

AF XY:

0.310

AC XY:

23045

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0887

AC:

3683

AN:

41536

American (AMR)

AF:

0.317

AC:

4842

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

1281

AN:

3466

East Asian (EAS)

AF:

0.325

AC:

1685

AN:

5184

South Asian (SAS)

AF:

0.385

AC:

1856

AN:

4822

European-Finnish (FIN)

AF:

0.469

AC:

4949

AN:

10560

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.390

AC:

26523

AN:

67962

Other (OTH)

AF:

0.308

AC:

649

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1511

3021

4532

6042

7553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.336

Hom.:

2887

Bravo

AF:

0.284

TwinsUK

AF:

0.374

AC:

1388

ALSPAC

AF:

0.354

AC:

1364

ESP6500AA

AF:

0.0953

AC:

419

ESP6500EA

AF:

0.390

AC:

3349

ExAC

AF:

0.362

AC:

43937

Asia WGS

AF:

0.331

AC:

1149

AN:

3478

EpiCase

AF:

0.379

EpiControl

AF:

0.381

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group I

Benign:4

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 10, 2021

Genome-Nilou Lab

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

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.

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.070

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.9

PhyloP100

5.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.96

REVEL

Benign

0.075

Sift

Benign

0.50

Sift4G

Uncertain

0.033

Polyphen

0.66

Vest4

0.18

MutPred

0.18

Gain of disorder (P = 0.0463)

MPC

0.016

ClinPred

0.023

GERP RS

4.9

Varity_R

0.11

gMVP

0.21

Mutation Taster

=91/9

polymorphism (auto)

(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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over