NM_001113378.2:c.257C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001113378.2(FANCI):c.257C>T(p.Ala86Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,612,532 control chromosomes in the GnomAD database, including 112,025 homozygotes. In-silico tool predicts 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. A86G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.30 ( 8212 hom., cov: 32)

Exomes 𝑓: 0.37 ( 103813 hom. )

Consequence

FANCI
NM_001113378.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.06

Publications

51 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 -16 ACMG points.

BP6

Variant 15-89260812-C-T is Benign according to our data. Variant chr15-89260812-C-T is described in ClinVar as Benign. ClinVar VariationId is 257484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCI	NM_001113378.2 link	c.257C>T	p.Ala86Val	missense_variant	Exon 4 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.257C>T	p.Ala86Val	missense_variant	Exon 4 of 38	1	NM_001113378.2	ENSP00000310842.8		Q9NVI1-3

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45344

AN:

151798

Hom.:

8212

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0881

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.309

Gnomad ASJ

AF:

0.369

Gnomad EAS

AF:

0.317

Gnomad SAS

AF:

0.374

Gnomad FIN

AF:

0.469

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.307

GnomAD2 exomes

AF:

0.360

AC:

90634

AN:

251442

AF XY:

0.369

show subpopulations

Gnomad AFR exome

AF:

0.0801

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.378

Gnomad EAS exome

AF:

0.319

Gnomad FIN exome

AF:

0.460

Gnomad NFE exome

AF:

0.380

Gnomad OTH exome

AF:

0.363

GnomAD4 exome

AF:

0.372

AC:

543699

AN:

1460616

Hom.:

103813

Cov.:

AF XY:

0.374

AC XY:

271711

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.0734

AC:

2457

AN:

33466

American (AMR)

AF:

0.355

AC:

15895

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.381

AC:

9963

AN:

26118

East Asian (EAS)

AF:

0.306

AC:

12138

AN:

39654

South Asian (SAS)

AF:

0.384

AC:

33098

AN:

86228

European-Finnish (FIN)

AF:

0.454

AC:

24189

AN:

53334

Middle Eastern (MID)

AF:

0.329

AC:

1897

AN:

5766

European-Non Finnish (NFE)

AF:

0.380

AC:

422231

AN:

1110996

Other (OTH)

AF:

0.362

AC:

21831

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

19250

38499

57749

76998

96248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13104

26208

39312

52416

65520

<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:

0.298

AC:

45337

AN:

151916

Hom.:

8212

Cov.:

AF XY:

0.306

AC XY:

22729

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.0879

AC:

3645

AN:

41474

American (AMR)

AF:

0.309

AC:

4716

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.369

AC:

1279

AN:

3470

East Asian (EAS)

AF:

0.318

AC:

1641

AN:

5164

South Asian (SAS)

AF:

0.375

AC:

1803

AN:

4804

European-Finnish (FIN)

AF:

0.469

AC:

4932

AN:

10510

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.386

AC:

26233

AN:

67912

Other (OTH)

AF:

0.305

AC:

644

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1494

2988

4483

5977

7471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.345

Hom.:

28945

Bravo

AF:

0.281

TwinsUK

AF:

0.370

AC:

1373

ALSPAC

AF:

0.353

AC:

1361

ESP6500AA

AF:

0.0948

AC:

417

ESP6500EA

AF:

0.384

AC:

3304

ExAC

AF:

0.357

AC:

43326

Asia WGS

AF:

0.312

AC:

1083

AN:

3478

EpiCase

AF:

0.375

EpiControl

AF:

0.378

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

Jan 12, 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

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

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

- -

not provided

Benign:2

Jul 05, 2018

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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

.;T;T;T;T;.;T

Eigen

Benign

-0.055

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

T;T;T;T;T;T;T

MetaRNN

Benign

0.0039

T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.2

M;M;.;.;.;M;.

PhyloP100

2.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.71

N;N;D;D;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.34

T;T;T;T;T;T;T

Sift4G

Benign

0.078

T;T;T;T;T;T;T

Polyphen

0.75

P;B;.;.;.;.;.

Vest4

0.13

MPC

0.019

ClinPred

0.014

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.075

gMVP

0.30

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.21

Position offset: 31

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