rs755403672

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001113378.2(FANCI):ā€‹c.3255T>Gā€‹(p.Cys1085Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,613,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.00010 ( 0 hom. )

Consequence

FANCI
NM_001113378.2 missense, splice_region

Scores

3
12
4
Splicing: ADA: 0.0006766
2

Clinical Significance

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

Conservation

PhyloP100: 0.880
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]
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FANCINM_001113378.2 linkuse as main transcriptc.3255T>G p.Cys1085Trp missense_variant, splice_region_variant 30/38 ENST00000310775.12 NP_001106849.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FANCIENST00000310775.12 linkuse as main transcriptc.3255T>G p.Cys1085Trp missense_variant, splice_region_variant 30/381 NM_001113378.2 ENSP00000310842 P1Q9NVI1-3

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000837
AC:
21
AN:
251020
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135808
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:
0.000185
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000102
AC:
149
AN:
1461092
Hom.:
0
Cov.:
32
AF XY:
0.000102
AC XY:
74
AN XY:
726856
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:
0.000130
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000900
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.000124
AC:
15
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000237

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), LabcorpJan 15, 2024This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 1085 of the FANCI protein (p.Cys1085Trp). This variant is present in population databases (rs755403672, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FANCI-related conditions. ClinVar contains an entry for this variant (Variation ID: 568595). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 GeneticsJul 26, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.78
BayesDel_addAF
Uncertain
0.045
T
BayesDel_noAF
Uncertain
0.10
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
.;T
Eigen
Uncertain
0.27
Eigen_PC
Benign
0.20
FATHMM_MKL
Benign
0.65
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.4
.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0050
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.77
MutPred
0.72
.;Loss of catalytic residue at L1086 (P = 0.0228);
MVP
0.92
MPC
0.11
ClinPred
0.46
T
GERP RS
3.6
Varity_R
0.74
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00068
dbscSNV1_RF
Benign
0.16
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: rs755403672; hg19: chr15-89848640; COSMIC: COSV105877485; COSMIC: COSV105877485; API