15-89281279-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_001113378.2(FANCI):ā€‹c.1491A>Gā€‹(p.Gln497Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,613,790 control chromosomes in the GnomAD database, including 1 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: š‘“ 0.00080 ( 0 hom., cov: 33)
Exomes š‘“: 0.00086 ( 1 hom. )

Consequence

FANCI
NM_001113378.2 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.00200
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
Variant 15-89281279-A-G is Benign according to our data. Variant chr15-89281279-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 317277.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr15-89281279-A-G is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.002 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FANCINM_001113378.2 linkuse as main transcriptc.1491A>G p.Gln497Gln synonymous_variant 15/38 ENST00000310775.12 NP_001106849.1 Q9NVI1-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FANCIENST00000310775.12 linkuse as main transcriptc.1491A>G p.Gln497Gln synonymous_variant 15/381 NM_001113378.2 ENSP00000310842.8 Q9NVI1-3

Frequencies

GnomAD3 genomes
AF:
0.000795
AC:
121
AN:
152208
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00113
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00125
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000986
AC:
248
AN:
251402
Hom.:
0
AF XY:
0.00102
AC XY:
139
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00218
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00108
Gnomad FIN exome
AF:
0.00166
Gnomad NFE exome
AF:
0.00117
Gnomad OTH exome
AF:
0.000815
GnomAD4 exome
AF:
0.000862
AC:
1260
AN:
1461464
Hom.:
1
Cov.:
31
AF XY:
0.000927
AC XY:
674
AN XY:
727024
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000470
Gnomad4 ASJ exome
AF:
0.00302
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00109
Gnomad4 FIN exome
AF:
0.00133
Gnomad4 NFE exome
AF:
0.000853
Gnomad4 OTH exome
AF:
0.000712
GnomAD4 genome
AF:
0.000801
AC:
122
AN:
152326
Hom.:
0
Cov.:
33
AF XY:
0.000752
AC XY:
56
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00113
Gnomad4 NFE
AF:
0.00125
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00108
Hom.:
0
Bravo
AF:
0.000759
EpiCase
AF:
0.00109
EpiControl
AF:
0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Fanconi anemia Benign:2
Likely benign, criteria provided, single submittercurationSema4, Sema4Apr 14, 2021- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Fanconi anemia complementation group I Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 22, 2021- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024FANCI: BP4, BP7 -
FANCI-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 06, 2019This 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
BayesDel_noAF
Benign
-0.51
CADD
Benign
1.1
DANN
Benign
0.56
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs145349375; hg19: chr15-89824510; API