NM_002025.4:c.3589G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

FRAXE intellectual disability
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

AFF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002025.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AFF2	NM_002025.4	MANE Select	c.3589G>A	p.Ala1197Thr	missense	Exon 19 of 21	NP_002016.2
AFF2	NM_001169123.2		c.3559G>A	p.Ala1187Thr	missense	Exon 19 of 21	NP_001162594.1
AFF2	NM_001169122.2		c.3484G>A	p.Ala1162Thr	missense	Exon 18 of 20	NP_001162593.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AFF2	ENST00000370460.7	TSL:5 MANE Select	c.3589G>A	p.Ala1197Thr	missense	Exon 19 of 21	ENSP00000359489.2
AFF2	ENST00000342251.7	TSL:1	c.3484G>A	p.Ala1162Thr	missense	Exon 18 of 20	ENSP00000345459.4
AFF2	ENST00000370457.9	TSL:1	c.3484G>A	p.Ala1162Thr	missense	Exon 18 of 20	ENSP00000359486.6

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

111496

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000384

AC:

AN:

182519

AF XY:

0.0000597

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 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

African (AFR)

AF:

0.000115

AC:

AN:

26134

American (AMR)

AF:

0.00

AC:

AN:

34840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18934

East Asian (EAS)

AF:

0.000101

AC:

AN:

29647

South Asian (SAS)

AF:

0.000114

AC:

AN:

52736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39593

Middle Eastern (MID)

AF:

0.000246

AC:

AN:

4059

European-Non Finnish (NFE)

AF:

0.00000601

AC:

AN:

832243

Other (OTH)

AF:

0.0000221

AC:

AN:

45257

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000117

AC:

AN:

111550

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33836

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

30720

American (AMR)

AF:

0.0000955

AC:

AN:

10474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.000280

AC:

AN:

3567

South Asian (SAS)

AF:

0.00

AC:

AN:

2617

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53129

Other (OTH)

AF:

0.00

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.567

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.83

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.77

M_CAP

Benign

0.0093

MetaRNN

Benign

0.033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.43

PhyloP100

0.47

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

REVEL

Benign

0.16

Sift

Benign

0.085

Sift4G

Benign

0.23

Polyphen

0.0040

Vest4

0.017

MVP

0.38

MPC

0.76

ClinPred

0.024

GERP RS

-8.7

Varity_R

0.083

gMVP

0.53

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over