chr15-89292997-G-C

Position:

chr15-89292997-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000310775.12(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. 13/20 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
ENST00000310775.12 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.96

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCI	NM_001113378.2 linkuse as main transcript	c.2225G>C	p.Cys742Ser	missense_variant	22/38	ENST00000310775.12	NP_001106849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCI	ENST00000310775.12 linkuse as main transcript	c.2225G>C	p.Cys742Ser	missense_variant	22/38	1	NM_001113378.2	ENSP00000310842	P1	Q9NVI1-3

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

GnomAD3 exomes

AF:

0.365

AC:

91607

AN:

251090

Hom.:

17823

AF XY:

0.373

AC XY:

50635

AN XY:

135736

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 SAS exome

AF:

0.391

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

Gnomad4 AFR exome

AF:

0.0740

Gnomad4 AMR exome

AF:

0.359

Gnomad4 ASJ exome

AF:

0.383

Gnomad4 EAS exome

AF:

0.313

Gnomad4 SAS exome

AF:

0.392

Gnomad4 FIN exome

AF:

0.455

Gnomad4 NFE exome

AF:

0.384

Gnomad4 OTH exome

AF:

0.366

GnomAD4 genome

AF:

0.302

AC:

45912

AN:

152130

Hom.:

8407

Cov.:

AF XY:

0.310

AC XY:

23045

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0887

Gnomad4 AMR

AF:

0.317

Gnomad4 ASJ

AF:

0.370

Gnomad4 EAS

AF:

0.325

Gnomad4 SAS

AF:

0.385

Gnomad4 FIN

AF:

0.469

Gnomad4 NFE

AF:

0.390

Gnomad4 OTH

AF:

0.308

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:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.070

.;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0025

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.9

M;M

MutationTaster

Benign

0.030

P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.96

N;N

REVEL

Benign

0.075

Sift

Benign

0.50

T;T

Sift4G

Uncertain

0.033

D;D

Polyphen

0.66

P;B

Vest4

0.18

MutPred

0.18

Gain of disorder (P = 0.0463);Gain of disorder (P = 0.0463);

MPC

0.016

ClinPred

0.023

GERP RS

4.9

Varity_R

0.11

gMVP

0.21

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

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