rs1302083447
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_000135.4(FANCA):āc.2738A>Cā(p.His913Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,068 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 Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
FANCA
NM_000135.4 missense
NM_000135.4 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 1.36
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939
PP5
Variant 16-89764930-T-G is Pathogenic according to our data. Variant chr16-89764930-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89764930-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.2738A>C | p.His913Pro | missense_variant | 28/43 | ENST00000389301.8 | NP_000126.2 | |
FANCA | NM_001286167.3 | c.2738A>C | p.His913Pro | missense_variant | 28/43 | NP_001273096.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.2738A>C | p.His913Pro | missense_variant | 28/43 | 1 | NM_000135.4 | ENSP00000373952.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
1
AN:
152204
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727234
GnomAD4 exome
AF:
AC:
2
AN:
1461864
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
727234
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
GnomAD4 genome
AF:
AC:
1
AN:
152204
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74346
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:4Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 24, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Jul 02, 2018 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Associated with slower hematologic disease progression - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 04, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 03, 2024 | - - |
Fanconi anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 913 of the FANCA protein (p.His913Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with Fanconi anemia (PMID: 29098742, 29269525). ClinVar contains an entry for this variant (Variation ID: 555969). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FANCA function (PMID: 29269525). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 12, 2019 | DNA sequence analysis of the FANCA gene demonstrated a sequence change, c.2621G>C in exon 28, which results in an amino acid change, p.Arg874Thr. The p.Arg874Thr change affects a highly conserved amino acid residue located in a domain of the FANCA protein that is not known to be functional. The p.Arg874Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL, in silico splice prediction programs). This sequence change is absent from large population databases such as ExAC and gnomAD. The p.Arg874Thr amino acid change occurs in a region of the FANCA gene where other missense sequence changes have been described in patients with FANCA-related disorders (PMIDs: 15643609, 24116929). This sequence change was identified with another likely pathogenic FANCA variant in a patient. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
D;D
Sift4G
Uncertain
D;D
Polyphen
B;.
Vest4
MutPred
Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at