rs144908351

Positions:

chr15-89281825-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 submissions are: {Uncertain_significance=2, Likely_benign=5, Benign=2}. Variant chr15-89281825-A-G is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCI	ENST00000310775.12 link	c.1573A>G	p.Met525Val	missense_variant	16/38	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

GnomAD3 exomes

AF:

0.00230

AC:

577

AN:

251280

Hom.:

AF XY:

0.00215

AC XY:

292

AN XY:

135812

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 SAS exome

AF:

0.000425

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

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000429

Gnomad4 FIN exome

AF:

0.00113

Gnomad4 NFE exome

AF:

0.00466

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00269

AC:

409

AN:

152282

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000943

Gnomad4 NFE

AF:

0.00404

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00356

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

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	FANCI: BP4, BS2 -

Fanconi anemia complementation group I

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 18, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jun 07, 2022	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. -

Fanconi anemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 02, 2020	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 08, 2021

- -

FANCI-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2022

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over