chrX-148661990-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_002025.4(AFF2):c.263A>G(p.His88Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,054 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )
Consequence
AFF2
NM_002025.4 missense
NM_002025.4 missense
Scores
2
2
13
Clinical Significance
Conservation
PhyloP100: 7.23
Genes affected
AFF2 (HGNC:3776): (ALF transcription elongation factor 2) This gene encodes a putative transcriptional activator that is a member of the AF4\FMR2 gene family. This gene is associated with the folate-sensitive fragile X E locus on chromosome X. A repeat polymorphism in the fragile X E locus results in silencing of this gene causing Fragile X E syndrome. Fragile X E syndrome is a form of nonsyndromic X-linked cognitive disability. In addition, this gene contains 6-25 GCC repeats that are expanded to >200 repeats in the disease state. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jul 2016]
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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=0.30751416).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AFF2 | NM_002025.4 | c.263A>G | p.His88Arg | missense_variant | 3/21 | ENST00000370460.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AFF2 | ENST00000370460.7 | c.263A>G | p.His88Arg | missense_variant | 3/21 | 5 | NM_002025.4 | P1 | |
AFF2 | ENST00000342251.7 | c.251A>G | p.His84Arg | missense_variant | 3/20 | 1 | |||
AFF2 | ENST00000370457.9 | c.263A>G | p.His88Arg | missense_variant | 3/20 | 1 | |||
AFF2 | ENST00000370458.5 | c.251A>G | p.His84Arg | missense_variant | 3/8 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD3 exomes AF: 0.00000545 AC: 1AN: 183370Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67832
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000182 AC: 2AN: 1096054Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 361524
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GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ExAC
?
AF:
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1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2020 | The alteration results in an amino acid change:_x000D_ _x000D_ The c.263A>G (p.H88R) alteration is located in coding exon 3 of the AFF2 gene. This alteration results from a A to G substitution at nucleotide position 263, causing the histidine (H) at amino acid position 88 to be replaced by an arginine (R). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the AFF2 c.263A>G alteration was observed in 0.0005% (1/183370) of total alleles studied, and none were hemizygous. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.H88 amino acid is conserved in available vertebrate species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.H88R alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;.;.;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;L
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.
REVEL
Uncertain
Sift
Benign
T;T;T;.
Sift4G
Benign
T;T;T;T
Polyphen
P;P;D;P
Vest4
MutPred
Gain of phosphorylation at T86 (P = 0.1185);.;.;Gain of phosphorylation at T86 (P = 0.1185);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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