rs118031800

Positions:

chr15-89295062-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001113378.2(FANCI):c.2604A>C(p.Glu868Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,551,968 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 28 hom. )

Consequence

FANCI
NM_001113378.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0930

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=0.0050183237).

BP6

Variant 15-89295062-A-C is Benign according to our data. Variant chr15-89295062-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 238317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89295062-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00266 (405/152318) while in subpopulation EAS AF= 0.0149 (77/5184). AF 95% confidence interval is 0.0122. There are 8 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCI	NM_001113378.2 linkuse as main transcript	c.2604A>C	p.Glu868Asp	missense_variant	24/38	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.2604A>C	p.Glu868Asp	missense_variant	24/38	1	NM_001113378.2	ENSP00000310842	P1	Q9NVI1-3

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

406

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0225

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000514

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00459

AC:

722

AN:

157468

Hom.:

AF XY:

0.00460

AC XY:

383

AN XY:

83268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000446

Gnomad ASJ exome

AF:

0.000353

Gnomad EAS exome

AF:

0.0134

Gnomad SAS exome

AF:

0.00571

Gnomad FIN exome

AF:

0.0235

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00197

AC:

2755

AN:

1399650

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

1432

AN XY:

690322

show subpopulations

Gnomad4 AFR exome

AF:

0.000348

Gnomad4 AMR exome

AF:

0.000504

Gnomad4 ASJ exome

AF:

0.000596

Gnomad4 EAS exome

AF:

0.0143

Gnomad4 SAS exome

AF:

0.00586

Gnomad4 FIN exome

AF:

0.0238

Gnomad4 NFE exome

AF:

0.000310

Gnomad4 OTH exome

AF:

0.00246

GnomAD4 genome

AF:

0.00266

AC:

405

AN:

152318

Hom.:

Cov.:

AF XY:

0.00362

AC XY:

270

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0149

Gnomad4 SAS

AF:

0.00476

Gnomad4 FIN

AF:

0.0225

Gnomad4 NFE

AF:

0.000514

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.00117

ExAC

AF:

0.00415

AC:

105

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FANCI: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 16, 2018

- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Fanconi anemia complementation group I

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.041

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.064

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.53

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.59

REVEL

Benign

0.032

Sift

Benign

1.0

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.055

MutPred

0.16

Gain of ubiquitination at K869 (P = 0.1586);

MVP

0.41

MPC

0.015

ClinPred

0.0083

GERP RS

2.9

Varity_R

0.047

gMVP

0.17

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