16-89765061-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000135.4(FANCA):​c.2607G>C​(p.Gln869His) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q869P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

FANCA
NM_000135.4 missense

Scores

4
12
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.90
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 Likely_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000135.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-89765062-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 215981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FANCANM_000135.4 linkuse as main transcriptc.2607G>C p.Gln869His missense_variant 28/43 ENST00000389301.8
FANCANM_001286167.3 linkuse as main transcriptc.2607G>C p.Gln869His missense_variant 28/43

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCAENST00000389301.8 linkuse as main transcriptc.2607G>C p.Gln869His missense_variant 28/431 NM_000135.4 P1O15360-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

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 testingInvitaeApr 03, 2017In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. A different missense substitution at this codon (p.Gln869Pro) has been reported in individuals affected with Fanconi anemia in the literature (PMID: 15643609) and in the Leiden Open-source Variation Database (PMID: 21520333), however, in some of these individuals, a second FANCA variant was not identified. In addition, an experimental study demonstrates that this variant may disrupt FANCA protein complex formation with FANCB and FANCL (PMID: 16720839). This suggests that the glutamine residue is may be critical for FANCA protein function. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FANCA-related disease. This sequence change replaces glutamine with histidine at codon 869 of the FANCA protein (p.Gln869His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.66
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.67
D;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.78
T;T
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
0.37
D
MutationAssessor
Uncertain
2.6
M;M
MutationTaster
Benign
0.91
D;D
PrimateAI
Benign
0.42
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Uncertain
0.63
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0090
D;D
Polyphen
1.0
D;.
Vest4
0.82
MutPred
0.37
Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP
0.95
ClinPred
0.94
D
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.44
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.41
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.41
Position offset: -15
DS_AL_spliceai
0.30
Position offset: 5

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: rs1555545583; hg19: chr16-89831469; API