16-89746857-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000135.4(FANCA):ā€‹c.3382C>Gā€‹(p.Gln1128Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000448 in 1,562,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000035 ( 0 hom. )

Consequence

FANCA
NM_000135.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 1.69
Variant links:
Genes affected
FANCA (HGNC:3582): (FA complementation group A) 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 A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24859214).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FANCANM_000135.4 linkuse as main transcriptc.3382C>G p.Gln1128Glu missense_variant 34/43 ENST00000389301.8 NP_000126.2
FANCANM_001286167.3 linkuse as main transcriptc.3382C>G p.Gln1128Glu missense_variant 34/43 NP_001273096.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FANCAENST00000389301.8 linkuse as main transcriptc.3382C>G p.Gln1128Glu missense_variant 34/431 NM_000135.4 ENSP00000373952 P1O15360-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152256
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000355
AC:
5
AN:
1410264
Hom.:
0
Cov.:
32
AF XY:
0.00000431
AC XY:
3
AN XY:
696772
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:
0.0000124
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000277
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152256
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria providedcurationLeiden Open Variation DatabaseFeb 28, 2020Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 08, 2021NM_000135.2(FANCA):c.3382C>G(Q1128E) is a missense variant classified as a variant of uncertain significance in the context of Fanconi anemia complementation group A. Q1128E has been observed in cases with relevant disease (PMID: 9371798). Functional assessments of this variant are available in the literature (PMID: 30057198, 12444097, 16946016). Q1128E has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000135.2(FANCA):c.3382C>G(Q1128E) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Fanconi anemia Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2022This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1128 of the FANCA protein (p.Gln1128Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 9371798). ClinVar contains an entry for this variant (Variation ID: 551847). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCA protein function. Experimental studies have shown that this missense change affects FANCA function (PMID: 16946016, 30057198). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jan 20, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.053
BayesDel_addAF
Uncertain
0.097
D
BayesDel_noAF
Benign
-0.10
CADD
Benign
14
DANN
Benign
0.96
DEOGEN2
Benign
0.14
T;.
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.42
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.56
T;T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.25
T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Benign
0.69
N;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.56
N;N
REVEL
Uncertain
0.48
Sift
Benign
0.13
T;T
Sift4G
Benign
0.14
T;T
Polyphen
0.0
B;.
Vest4
0.19
MutPred
0.70
Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP
0.93
ClinPred
0.079
T
GERP RS
4.1
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
2.1
Varity_R
0.036
gMVP
0.18

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: rs1439817346; hg19: chr16-89813265; API