rs373659849

Positions:

chrX-148980756-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_002025.4(AFF2):c.3589G>A(p.Ala1197Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,194,993 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.000018 ( 0 hom. 9 hem. )

Consequence

AFF2
NM_002025.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.471

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:

AFF2 (HGNC:):

AFF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032989204).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000117 (13/111550) while in subpopulation AFR AF= 0.000358 (11/30720). AF 95% confidence interval is 0.0002. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AFF2	NM_002025.4 linkuse as main transcript	c.3589G>A	p.Ala1197Thr	missense_variant	19/21	ENST00000370460.7	NP_002016.2	P51816-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AFF2	ENST00000370460.7 linkuse as main transcript	c.3589G>A	p.Ala1197Thr	missense_variant	19/21	5	NM_002025.4	ENSP00000359489.2		P51816-1

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

111496

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33772

show subpopulations

Gnomad AFR

AF:

0.000359

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000956

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

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

GnomAD3 exomes

AF:

0.0000384

AC:

AN:

182519

Hom.:

AF XY:

0.0000597

AC XY:

AN XY:

67017

show subpopulations

Gnomad AFR exome

AF:

0.0000761

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000725

Gnomad SAS exome

AF:

0.000106

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000175

AC:

AN:

1083443

Hom.:

Cov.:

AF XY:

0.0000257

AC XY:

AN XY:

350875

show subpopulations

Gnomad4 AFR exome

AF:

0.000115

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000114

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000601

Gnomad4 OTH exome

AF:

0.0000221

GnomAD4 genome

AF:

0.000117

AC:

AN:

111550

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33836

show subpopulations

Gnomad4 AFR

AF:

0.000358

Gnomad4 AMR

AF:

0.0000955

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.3589G>A (p.A1197T) alteration is located in exon 19 (coding exon 19) of the AFF2 gene. This alteration results from a G to A substitution at nucleotide position 3589, causing the alanine (A) at amino acid position 1197 to be replaced by a threonine (T). 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

0.067

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.83

DANN

Benign

0.77

DEOGEN2

Benign

0.23

T;.;.;.

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.0093

MetaRNN

Benign

0.033

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.43

N;.;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

N;.;N;N

REVEL

Benign

0.16

Sift

Benign

0.085

T;.;T;T

Sift4G

Benign

0.23

T;T;T;T

Polyphen

0.0040

B;B;B;.

Vest4

0.017

MVP

0.38

MPC

0.76

ClinPred

0.024

GERP RS

-8.7

Varity_R

0.083

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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