chr15-89247648-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_001113378.2(FANCI):ā€‹c.1A>Gā€‹(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

FANCI
NM_001113378.2 start_lost

Scores

5
8
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.08
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_001113378.2 (FANCI) was described as [Pathogenic] in ClinVar as 929712
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FANCINM_001113378.2 linkuse as main transcriptc.1A>G p.Met1? start_lost 2/38 ENST00000310775.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCIENST00000310775.12 linkuse as main transcriptc.1A>G p.Met1? start_lost 2/381 NM_001113378.2 P1Q9NVI1-3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251438
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461538
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 27, 2021This sequence change affects the initiator methionine of the FANCI mRNA. The next in-frame methionine is located at codon 94. This variant is present in population databases (rs781249928, ExAC 0.001%). Disruption of the initiator codon has been observed in individual(s) with Fanconi anemia (PMID: 17452773). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Fanconi anemia complementation group I Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 16, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.27
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
.;T;T;T;T;.;T
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.38
D
MutationTaster
Benign
1.0
D;D;D;D
PROVEAN
Benign
-1.5
N;N;N;N;N;N;N
REVEL
Uncertain
0.63
Sift
Uncertain
0.026
D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D
Polyphen
0.92
P;D;.;.;.;.;.
Vest4
0.67
MutPred
1.0
Loss of ubiquitination at K4 (P = 0.0506);Loss of ubiquitination at K4 (P = 0.0506);Loss of ubiquitination at K4 (P = 0.0506);Loss of ubiquitination at K4 (P = 0.0506);Loss of ubiquitination at K4 (P = 0.0506);Loss of ubiquitination at K4 (P = 0.0506);Loss of ubiquitination at K4 (P = 0.0506);
MVP
0.87
ClinPred
0.95
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.19
gMVP
0.60

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.

Other links and lift over

dbSNP: rs781249928; hg19: chr15-89790879; API