chr15-89247659-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001113378.2(FANCI):​c.12G>C​(p.Lys4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

FANCI
NM_001113378.2 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2671368).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FANCINM_001113378.2 linkuse as main transcriptc.12G>C p.Lys4Asn missense_variant 2/38 ENST00000310775.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCIENST00000310775.12 linkuse as main transcriptc.12G>C p.Lys4Asn missense_variant 2/381 NM_001113378.2 P1Q9NVI1-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 06, 2021In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with FANCI-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with asparagine at codon 4 of the FANCI protein (p.Lys4Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.031
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
.;T;T;T;T;.;T
Eigen
Benign
0.11
Eigen_PC
Benign
0.061
FATHMM_MKL
Benign
0.57
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D;D
M_CAP
Uncertain
0.095
D
MetaRNN
Benign
0.27
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Uncertain
2.6
M;M;.;.;.;M;.
MutationTaster
Benign
0.95
D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-1.6
N;N;N;N;N;N;N
REVEL
Uncertain
0.31
Sift
Uncertain
0.0040
D;D;D;D;D;D;D
Sift4G
Uncertain
0.0090
D;D;D;D;D;D;D
Polyphen
1.0
D;D;.;.;.;.;.
Vest4
0.50
MutPred
0.16
Loss of ubiquitination at K4 (P = 0.0074);Loss of ubiquitination at K4 (P = 0.0074);Loss of ubiquitination at K4 (P = 0.0074);Loss of ubiquitination at K4 (P = 0.0074);Loss of ubiquitination at K4 (P = 0.0074);Loss of ubiquitination at K4 (P = 0.0074);Loss of ubiquitination at K4 (P = 0.0074);
MVP
0.83
MPC
0.072
ClinPred
0.83
D
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.23
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-89790890; API