X-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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.23

Variant links:

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]

AFF2 links:

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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 linkuse as main transcript	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 linkuse as main transcript	c.263A>G	p.His88Arg	missense_variant	3/21	5	NM_002025.4	P1	P51816-1
AFF2	ENST00000342251.7 linkuse as main transcript	c.251A>G	p.His84Arg	missense_variant	3/20	1			P51816-3
AFF2	ENST00000370457.9 linkuse as main transcript	c.263A>G	p.His88Arg	missense_variant	3/20	1			P51816-6
AFF2	ENST00000370458.5 linkuse as main transcript	c.251A>G	p.His84Arg	missense_variant	3/8	1			P51816-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183370

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1096054

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361524

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.12

T;.;.;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.82

L;.;.;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.2

N;N;N;.

REVEL

Uncertain

0.30

Sift

Benign

0.87

T;T;T;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.89

P;P;D;P

Vest4

0.27

MutPred

0.48

Gain of phosphorylation at T86 (P = 0.1185);.;.;Gain of phosphorylation at T86 (P = 0.1185);

MVP

0.63

MPC

0.66

ClinPred

0.41

GERP RS

5.6

Varity_R

0.51

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over